MD Pauline ; Guillouche

Imad

MD Cyrille Feray

Systematic Review: antiviral therapy of recurrent hepatitis C post liver transplant

published or not. The documents may come   L'archive ouverte pluridisciplinaire

Introduction

In addition to alcoholic cirrhosis, Hepatitis C virus (HCV)-related cirrhosis is, a major indication for liver transplantation (LT) worldwide. It is the second most common indication for transplantation in northern Europe and in the USA and the primary indication in countries with high HCV seroprevalence such as Italy or Spain. Indications are end-stage liver diseases and/or hepatocellular carcinoma (HCC). Patients in the former group are usually placed high on the waiting list based on the prognostic MELD score (Model for End-stage Liver Disease) [START_REF] Kamath | A model to predict survival in patients with end-stage liver disease[END_REF]. Patients in the latter group with preserved liver function usually wait for a long period and must be treated for HCC. After transplantation, recurrence of HCV infection occurs in almost all patients (2) (3) and is associated with reduced graft and patient survival (4) [START_REF] Berenguer | Natural history of recurrent hepatitis C[END_REF]. However, survival of patients after transplantation who become serum HCV RNA negative during therapy was improved [START_REF] Picciotto | Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation[END_REF].

Recurrence of infection is immediate in recipients who are serum HCV RNApositive at liver transplantation [START_REF] Gane | A longitudinal analysis of hepatitis C virus replication following liver transplantation[END_REF]. It does not occur in the few patients who experience a sustained virological response (SVR) to antiviral therapy before transplantation. Acute hepatitis is unpredictable, frequently asymptomatic and usually appears between 1 and 6 months after LT. In less than 5 % of patients, acute recurrence is severe, corresponding to a fibrosing cholestatic hepatitis (FCH) which is also described in other settings of immunosuppression. Once established, FCH leads to liver failure in a few weeks or months. More frequently up to 20 % of patients transplanted for HCV-liver disease may have no significant lesions 5 years after LT (8) [START_REF] Gane | Longterm outcome of hepatitis C infection after liver transplantation[END_REF]. Thus, changes consistent with chronic, mild hepatitis are usually observed in more than 70 % of cases in the 5 years after LT [START_REF] Feray | The course of hepatitis C virus infection after liver transplantation[END_REF]. A ten to 20 fold increase in HCV viral load is generally observed in the first year following LT [START_REF] Gane | A longitudinal analysis of hepatitis C virus replication following liver transplantation[END_REF], with a subsequent decrease to levels found in immunocompetent subjects.

Recurrent liver disease is clearly more aggressive after LT than in immunocompetent subjects, as progression to cirrhosis at 5 years occurs in 10 to 50 % of LT patients (9) [START_REF] Berenguer | HCV-related fibrosis progression following liver transplantation: increase in recent years[END_REF] while in immunocompetent subjects decades of infection are required before cirrhosis develops. Once cirrhosis is established, the probability of liver graft failure is 42 % within 12 months [START_REF] Berenguer | Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients[END_REF]. Theoretically, there is a risk of developing a new HCC on the liver graft but, to our knowledge, this has never been reported.

The progression of recurrent HCV is variable and the risk factors are the subject of debate. Many factors have been reported to play a role before LT (genotype 1 [START_REF] Feray | European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group[END_REF], viral load and female gender), or after LT (time of cold or warm ischemia [START_REF] Watt | Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome[END_REF], blood transfusions, steatosis on the liver graft, age of the donor, use of antilymphocytes [START_REF] Rosen | Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation[END_REF], co-infection with HIV (15) ). Amongst these factors, donor age appears to be a major indicator of a poor prognosis of recurrent hepatitis C because donor-age is increasing (11) [START_REF] Berenguer | Hepatitis C and liver transplantation[END_REF] . However, donor age is also important in non-HCV patients [START_REF] Rifai | Donor age influences 10year liver graft histology independently of hepatitis C virus infection[END_REF]. Data from large registries indicate that the recurrence of HCV probably results in decreased survival as compared to other indications (18) [START_REF] Gringeri | Hepatitis C virus-related cirrhosis as a significant mortality factor in intention-to-treat analysis in liver transplantation[END_REF].

HCV recurrence appears to have the poorest prognosis of all causes of retransplantation with a 2-year survival rate of less than 33 % (20) (21) [START_REF] Ercolani | Histological recurrent hepatitis C after liver transplantation: Outcome and role of retransplantation[END_REF].

Mortality is frequently high in the first year after retransplantation [START_REF] Carmiel-Haggai | Recurrent hepatitis C after retransplantation: factors affecting graft and patient outcome[END_REF]. In a study by Berenguer (20), only 4 (33 %) of 12 patients who underwent retransplantation for HCV cirrhosis on the first graft survived after 2 years of follow-up. Causes of death were HCV cirrhosis in 2 patients, FCH in one and surgical complications in 3 patients. Retrospective studies (23) [START_REF] Pelletier | Hepatitis C is a risk factor for death after liver retransplantation[END_REF] have shown that HCV infection is an independent risk factor of mortality after retransplantation. Re-transplant recipients with HCV infection had a higher death rate compared to non-HCV retransplant recipients (26.0 vs. 8.8 deaths/100 patient-years, respectively) [START_REF] Pelletier | Hepatitis C is a risk factor for death after liver retransplantation[END_REF].

One reason for this could be a delayed indication for retransplantation after unsuccessful antiviral therapies [START_REF] Berenguer | Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus-related graft cirrhosis[END_REF] in patients with co-morbidities. Only one retrospective study [START_REF] Ghabril | Liver retransplantation of patients with hepatitis C infection is associated with acceptable patient and graft survival[END_REF] did not show any significant difference between HCV and non-HCV patients after retransplantation with a 3-year survival rate of 67 % and 66 % respectively.

Methods

The information for this review was compiled by searching PubMed and MEDLINE databases (1990 to 2010). The search terms used were "liver transplantation", "HCV recurrence", "treatment of recurrence", "randomized trials". Priority was given to randomized and controlled studies. The web of science and clinical trials.gov were also searched to identify ongoing

Interferon-alfa and ribavirin therapy

Classic antiviral therapies based on pegylated interferon-alfa and ribavirin may be indicated before LT to avoid recurrence, systematically after liver transplantation (pre-emptive therapy) or later once chronic hepatitis has been confirmed and immunosuppression is relatively low. Before or after LT, combined bitherapy has clear limitations: poor tolerance, poor efficacy and serious adverse events.

Therapy before LT

In the past decade, combined therapy with interferon-alfa and ribavirin has improved. An increasing number of patients with cirrhosis who would have been previously excluded can now be treated thanks to pegylated interferon-alpha (PEG-IFN), the use of granulocyte and erythrocyte growth factors, and dosing of ribavirin. Veldt et al [START_REF] Veldt | Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis[END_REF] studied 479 patients with compensated cirrhosis. One hundred and forty two of these patients experienced a sustained virological response (SVR) (30 %) and had significantly fewer liver-related deaths or HCC.

Thus this bitherapy may be tempting in candidates with compensated liver disease waiting for LT due to HCC, especially those with HCV genotypes 2 or 3 when the waiting list is long, or if they are naive or relapsers. Another recent prospective and randomised clinical trial [START_REF] Bruno | Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis[END_REF] confirmed that SVR was lower in patients with cirrhosis (33%) than in those with bridging fibrosis (51%-p=0.0028). All patients with cirrhosis had compensated liver disease defined by a Child-Pugh score <7. Tolerance to antiviral therapy was similar in patients with and without bridging fibrosis or cirrhosis.

In decompensated cirrhosis, therapy is less effective and even hazardous. In a randomised study of 129 patients with an average MELD score of 14 by Lacobellis et al (28) SVR was 43 % in patients infected with HCV genotype 2 or 3 and only 7 % in those infected with genotype 1. One of the goals of treating decompensated patients on the waiting list is to achieve plasma HCV RNAnegativity at LT. In the study by Everson (29) Forns (30) suggesting that post -transplant recurrence can be prevented in up to 20 % of selected patients.

Pre-emptive treatment (Table I)

The aim of this approach is to rapidly prevent the development of chronic hepatitis once the patient has been transplanted before there is biochemical and histological evidence of recurrent HCV infection. Although treatment of acute hepatitis is very effective in immunocompetent subjects (31) recurrent hepatitis C after liver transplantation is clearly not an acute infection. In contrast, immunosuppression is strong the first year after LT, which probably decreases the antiviral response during this period. The initial pilot study by Mazzafero et al [START_REF] Mazzaferro | Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment[END_REF] reported encouraging effects with 12-month, pre-emptive treatment in 36 LT patients with a combination of non-pegylated IFN alfa and ribavirin for one year, beginning within 3 weeks after LT. Serum HCV -RNA clearance was obtained in 12 (33 %) patients after 37 days of treatment. At the end of the one-year period all of these 12 patients remained HCV-RNA negative. Dose reductions were frequent but none of the patients was withdrawn from treatment and there was no graft rejection during the study.

Four randomized studies have evaluated monotherapy with non-Pegylated (33) [START_REF] Sheiner | The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation[END_REF] or PEG-IFN alfa [START_REF] Chalasani | Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials[END_REF], and only one has evaluated the combination of interferon alfa or PEG-IFN alfa plus Ribavirin [START_REF] Shergill | Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation[END_REF]. SVR was achieved in less than 20 % in all of these studies and there were numerous side effects because only a minority of patients could receive a full-dose treatment. Conversely, the severity of recurrence was decreased in most of these studies. Therefore preemptive treatment is a strategy to be explored and final results of prospective, randomized studies are expected. In particular, the PHOENIX trial prospectively compared pre-emptive therapy and the treatment of recurrent liver disease. the intention to treat analysis, (SVR) was achieved by 12/54 (22%) patients in the prophylaxis arm and 3/14 (21%) treated patients in the observation arm. In the intention to treat analysis, 34/55 (62%) patients in the prophylaxis arm versus 39/60 (65%) patients in the observation arm developed recurrent hepatitis C. Withdrawal during the 48-week treatment/observation period was frequent: 24 patients in the prophylaxis arm and 17 patients in the observation arm. Prophylactic treatment with PEG-IFN alfa-2a/ribavirin to prevent recurrent hepatitis C was associated with a low rate of SVR, side-effects, and a high rate of discontinuation [START_REF] Charlton | Prophylactic peginterferon alfa-2a/ribavirin vs no prophylaxis following orthoptic liver transplantation for hepatitis C: 24 weeks virologic and safety responses[END_REF].

Treatment of recurrent chronic hepatitis (Table II)

In many transplantation centres, antiviral treatment is delayed until there is histological evidence of recurrent hepatitis. Definition of histological HCV recurrence can range from simple lobular hepatitis (F0) to more severe, chronic hepatitis with fibrosis, as well as the relatively rare, but severe, fibrosing cholestatic hepatitis [START_REF] Carrion | Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study[END_REF]. This therapeutic approach has been reported in 8 small, randomised trials (35) (38) (39) (40) (41) (42) (43) [START_REF] Angelico | A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C[END_REF]. Antiviral treatment was begun between 6 and 60 months after liver transplantation. All of the results of trials using IFN-alfa monotherapy were disappointing with less than 12 % of SVR and no benefit in treated patients (40) (42) [START_REF] Chalasani | Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials[END_REF]. In contrast, in studies with the combination of IFN-alfa and Ribavirin (41) (45) (46) [START_REF] Samuel | Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study[END_REF] and, more recently PEG-IFN plus ribavirin (47) (48) (49) (50) (51) (52) (6) [START_REF] Carrion | Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study[END_REF] [START_REF] Balbi | Treatment for recurrent hepatitis C virus infection after liver transplantation[END_REF], SVR was achieved in between 20 % (43) and 30 % (38) respectively. Improvement in necroinflammatory activity and fibrosis was more likely in patients who achieved SVR with combination therapy, and the likelihood of developing cirrhosis was significantly reduced compared to patients who did not achieve SVR [START_REF] Bizollon | Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C[END_REF]. Finally, recent, unpublished reports suggest that 5-year survival rates are higher in patients who achieve SVR, as well as in those who experience relapse than in non -responders (96 % and 93 % versus 83 %) [START_REF] Lilly | Improved survival in liver transplant recipients (LT) treated for recurrent hepatitis C (HCV) is seen in both relapsers and in sustained responders[END_REF].

Predictors of SVR seem to be the same as in the non-transplant setting. In a retrospective study Hanouneh et al [START_REF] Hanouneh | Recurrent hepatitis C after liver transplantation: ontreatment prediction of response to peginterferon/ribavirin therapy[END_REF] found that a rapid virological response (e.g. undetectable viral load at week 4) was a good predictor of SVR with a very high specificity and positive predictive value. Four other studies (50) (51) [START_REF] Carrion | Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study[END_REF] (57) confirmed that most, if not all, patients who achieved SVR had a virological response at week 12. The second important factor affecting treatment response was obviously viral genotype with a poor response in genotype 1 patients (48) [START_REF] Hanouneh | Recurrent hepatitis C after liver transplantation: ontreatment prediction of response to peginterferon/ribavirin therapy[END_REF]. Another important factor is the presence of FCH, which is almost incurable with IFN bitherapy [START_REF] Carrion | Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study[END_REF].

Another strong predictor of SVR is adverse events. There were fewer dose reductions in patients with SVR [START_REF] Sharma | Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence[END_REF]. Thrombocytopaenia, neutropenia, or anaemia may require a dose reduction, discontinuation or stopping therapy. These effects were very common with therapy in all trials, leading to cessation of therapy in up to 43 % of treated patients [START_REF] Samuel | Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study[END_REF]. The prospective study by Calmus (58) clearly demonstrated that ribavirin was mandatory throughout the entire course of treatment. Fortunately the use of G-CSF and EPO has improved tolerance to treatment, reducing cytopenia so that antiviral therapy can be maintained.

Rejection induced by interferon alfa (Table III)

Chronic rejection was initially described with monotherapy using non-pegylated IFN-alfa [START_REF] Feray | The course of hepatitis C virus infection after liver transplantation[END_REF]. It seems to be far less frequent (<5%) with combined therapies.

Ribavirin, which has immunomodulatory effects, could explain the lower rate of rejection. Better patient selection, improvement of immuno suppressive regimens and careful histological follow-up also probably play a role in the low rate of rejection.

Immunosuppression and HCV (Table IV)

During the first post-transplant months, serum HCV-RNA levels increase when immunosuppression is the highest. The relationship between HCV recurrence, its severity and the type of immunosuppressive regimen remain unclear.

Because the distinction between recurrent hepatitis and rejection is far from clear-cut, the effect of immunosuppression on recurrent hepatitis is difficult to assess. It has been clearly established that the induction of immunosuppression through antilymphocyte antibodies is deleterious [START_REF] Rosen | Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation[END_REF]. Cyclosporine A (CyA) has been shown to suppress in cultured hepatocytes, the replication of HCV through the interaction of cyclophylin A and the NS2 viral protein [START_REF] Watashi | Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes[END_REF]. Most prospective (62) (63) (64) (65) studies suggest that there is no difference between cyclosporine-based regimens and tacrolimus-based regimens for liver histology or long-term graft survival. A meta-analysis (66) of randomised clinical trials did not find any statistically significant difference in mortality, graft survival, acute rejection or FCH between the two immunosuppressive regimens. On the other hand, 3 studies have suggested that SVR rates were higher in patients receiving cyclosporine compared to those receiving mycophenolate mofetil (MMF) or tacrolimus (67) (68) [START_REF] Carrion | Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study[END_REF]. A recent report from Italy has confirmed that cyclosporine may be associated with a higher rate of SVR compared to tacrolimus in patients receiving IFN alfabased combination therapy for recurrent hepatitis C after liver transplantation (39.5 % versus 13.2 %) [START_REF] Cescon | Viral genotype, immunosuppressio with cyclosporine and donor age predict sustained viro logical response after antiviral treatment for hepatitis recurrence following liver transplantation[END_REF].

Finally in a randomised trial in 2002 Jain et al [START_REF] Jain | A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C[END_REF] concluded that there was no difference in HCV recurrence, patient survival or rejection between a regimen of tacrolimus and tacrolimus plus MMF. However another retrospective report [START_REF] Wiesner | Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C[END_REF] showed that the addition of MMF at discharge to tacrolimus-based immunosuppression was associated with improved long-term outcomes after liver transplantation in patients with HCV.

Treament of HCV -recurrence in HIV-HCV co-infected patients

With the introduction of highly active antiretroviral therapies, replication of HIV is controlled and liver transplantation is feasible. The main difficulty after LT in these cases is severe recurrence of HCV [START_REF] Duclos-Vallee | Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus[END_REF].

HIV infection accelerates the progression of recurrent HCV (72) and probably affects survival in transplanted co-infected patients (73) [START_REF] Wojcik | Antiviral therapy for hepatitis C virus recurrence after liver transplantation in HIVinfected patients: outcome in the Bonn cohort[END_REF]. Some studies have shown that recurrent HCV in these patients increased the incidence of FCH, a leading cause of mortality (73) [START_REF] Radecke | Outcome after orthotopic liver transplantation in five HIV-infected patients with virus hepatitis-induced cirrhosis[END_REF]. HCV recurrence increases the mitochondrial toxicity of antiretrovirals which is not observed in HIV-HBV coinfected patients [START_REF] Tateo | Long-term follow-up of liver transplanted HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication and absence of mitochondrial toxicity[END_REF]. However because of the significant toxicities and drugto-drug interactions of nucleoside reverse transcriptase inhibitors in combination with ribavirin, with drug-to-drug interaction of HIV protease inhibitors with HCV protease inhibitors and calcineurin-inhibitors, new There are few studies on the treatment of recurrent HCV in co-infected patients and all of them are uncontrolled and non-randomized with small patient populations. Castells et al [START_REF] Castells | Early antiviral treatment of hepatitis C virus recurrence after liver transplantation in HIV-infected patients[END_REF] investigated the efficacy of early antiviral treatment for recurrent HCV in co-infected patients. Treatment with PEG-IFN alfa 2b and ribavirin was administered for 24 to 48 weeks when histological recurrence was observed. Three of the 5 patients presented with severe cholestatic hepatitis. Antiviral treatment was initiated a median of 12 weeks after LT. SVR was only achieved in one patient. The antiretroviral regimen was not modified in any of the patients. Moreover, acute rejection or mitochondrial toxicity was not observed. In contrast, in the study by Wojcik (74), four coinfected patients with recurrent HCV after LT received peg-IFN plus ribavirin for 6 to 12 months. FCH hepatitis was diagnosed in 2 patients. At the end of the treatment, all patients were HCV-RNA negative with improved histology.

Specific targeted antiviral therapies (STAT-C)

Specific targeted antiviral therapies directed against protease, polymerase or other non structural proteins will certainly change the prognosis of recurrent hepatitis C after LT. The two molecules directed against viral protease NS3 in the most advanced stages of development (telaprevir and boceprevir) combined with classic bitherapy have been shown to increase the SVR in naïve patients, relapsers and non responders (77) (78) [START_REF] Kwo | C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial[END_REF]. Although these treatments will be soon available to immunocompetent patients no reports exist for transplanted patients. STAT-C induced rapid selection of the escape mutant and must be used in combination with classical bitherapy. Interaction with immunosuppressive drugs and additional adverse events will probably limit the use of this treatment. Another very interesting perspective is the combination of antiprotease and antipolymerase molecules without interferon-alfa or ribavirin (80) which was tested in immunocompetent patients in a short-term trial.

Prediction of SVR in liver transplant patients

Blockage of HCV cell entry

Viral entry is required for the initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The first way to block entry is obviously by neutralizing HCV. Chimpanzees inoculated with infectious plasma (83) and more recently immunodeficient mice harboring human hepatocytes (84) are the two animal models for HCV. More recently, the JFH1 HCV strain (85) which can infect hepatocyte cell lines (Huh7) has been used to test viral neutralization of clinical sera (86) [START_REF] Castelain | Low levels of hepatitis C virus (HCV) neutralizing antibodies in patients coinfected with HCV and human immunodeficiency virus[END_REF]. Antibody-mediated neutralization has also been suggested in chimpanzees [START_REF] Farci | Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein[END_REF] or in patients receiving different preparations of polyclonal immunoglobulins [START_REF] Feray | Incidence of hepatitis C in patients receiving different preparations of hepatitis B immunoglobulins after liver transplantation[END_REF]. During the chronic phase of HCV infection, most HCV-infected patients develop high-titer cross-neutralizing antibodies (85) [START_REF] Vanwolleghem | Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver-chimeric mice from infection with a homologous hepatitis C virus strain[END_REF]. However, the small trial using polyclonal anti-HCV preparations (HCIG) after LT was shown to be both innocuous and ineffective [START_REF] Davis | A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients[END_REF].

Another exiting approach is to block cell entry at the level of cell receptors. The

Conclusions

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  studies. Finally we selected interesting recent papers on the treatment of recurrent hepatitis C.

  This as yet unpublished trial (ClinicalTrials.gov NCT00087633) measured the efficacy, tolerance, and safety of PEG-IFN alfa-2a/ribavirin prophylaxis in preventing recurrent allograft hepatitis C. At 10-26 weeks post-OLT, 115 patients were randomized to either 48 weeks of peginterferon alfa-2a plus ribavirin or observation. Patients in the observation arm who developed histological recurrence of HCV were treated with PEG-IFN alfa-2a/ribavirin. In

  Two meta-analyses (59) (60) have shown that steroid-free protocols are significantly better in limiting the recurrence of HCV [R.R = 1.15 (1.01, 1.13)], acute graft hepatitis [O.R = 3.15 (1.18, 8.40)] and treatment failure [O.R = 1.87 (1.33, 2.63)] (60).

  interactions could be attractive therapeutic alternatives for post-liver transplantation.

tight junction protein claudin- 1 (

 1 CLDN1) has been shown to be necessary for entry of HCV into the cell. Monoclonal antibodies against the HCV entry factor CLDN1 has been shown to be effective in a model of cultured human hepatocytes[START_REF] Fofana | Monoclonal anticlaudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes[END_REF] and might be effective in preventing HCV recurrence after well as in limiting viral spread in chronically infected patients. The potential drawback of this new approach could be the side-effects induced by antibodies directed against these cell receptors. The major advantage of this approach is that the selection of viral mutations is unlikely.Blocking either viral or cell receptors could be ineffective in case of high viral load. Neutralizing anti-HBs (HBIG) in HBV does not prevent post-LT recurrence in patients with high viral load at LT while HBIG has been shown to be effective in patients with either spontaneous low HBV viremia or those receiving antiretroviral therapy. Hypothetically, neutralization and reduction of viral load could prevent recurrent HCV infection.

  , there was no post-transplant

	recurrence in 12/15 (80%) HCV RNA -negative recipients. Results were lower in
	the study by
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  interferon alfa and ribavirin showed that the DNA polymorphism of the IL28 gene, a type-I cytokine involved in the antiviral response, is a powerful predictor of SVR[START_REF] Thomas | Genetic variation in IL28B and spontaneous clearance of hepatitis C virus[END_REF]. As a result of this major finding the SVR can be predicted for genotype 1 as well as genotype 3 HCV patients. Moreover, favourable polymorphisms seem to correspond to a higher expression of this cytokine in the liver. Liver transplantation is an interesting model since the polymorphisms of both the recipient and the donor could be involved. Very recent small series in patients with recurrent HCV after LT, suggest that donor or recipient IL28B genotypes could predict SVR with PEG-IFN/RBV therapy. The first published series on this subject[START_REF] Fukuhara | Variants in IL28B in liver recipients and donors correlate with response to peginterferon and ribavirin therapy for recurrent hepatitis C[END_REF] suggested that recipient and donor IL28B status are related to SVR after LT. Larger series are clearly required to determine the respective role of donor or recipient polymorphisms. If the donor genotype is really predictive, livers from donors with favorable polymorphisms could be directed to HCV recipients.

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Large genome-wide association studies of immunocompetent patients infected with genotype 1 HCV and treated in controlled trials by classic pegylated

TABLE I : PREEMPTIVE TREATMENT: PROSPECTIVE AND RANDOMISED STUDIES

 I

		Transplantation
	Study	treatment interval	Antiviral therapy, time	N	Withdrawals	Virological response	Histological results	Adverse events
		(weeks)
							HCV recurrence: 50% in the
	Singh et al Transplantation 1998	<2	IFN 3MU tiw vs no treatment 24 weeks	24	nd	0 in both groups	IFN group vs 42% in the control group (NS) No difference in severity of	IFN group: Leukopenia (17%) asthenia (33%)
							recurrence
	Sheiner et al Hepatology 1998	<2	IFN 3MU tiw vs no treatment 48 weeks	71	discontinuation: 14%	ETR: IFN 17% control: 5% NS	Incidence of early recurrence reduced in IFN group: 26% vs 54% in control group (p=.017)	IFN group: Thrombocytopenia (17%)
	Shergill et al American journal of Transplantation 2005	<6	IFN 3MU tiw OR Peg-IFN 1,5 µg/kg vs IFN + Ribavirin 600 to 1-1,2mg/day 48 weeks	44	discontinuation: 41%	SVR: IFN 4,54% IFN+RIB 18,2% NS	nd	27% serious adverse events 11 received growth factors Hemolytic anemia with Ribavirin
	Chalasani et al Hepatology 2005	<3	Peg-IFN 180µg/week vs no treatment 48 weeks	54	Withdrawals:31% Dose reductions: 42%	SVR: IFN: 8% No treatment: 0 NS	HAI score and fibrosis are lower in IFN group But not significant	IFN group: Thrombocytopenia or anemia 9%
	Abbreviations:

N: number of patients, IFN: Interferon, Peg: pegylated, tiw: three times weekly, ETR: undetectable hepatitis C virus RNA at the end of treatment, SVR: sustained virological response, HAI: histology activity index, nd: not defined, ns: not statistically significant.

TABLE II : TREATMENT OF HEPATITIS C RECURRENCE: PROSPECTIVE AND RANDOMISED STUDIES

 II of patients, IFN: Interferon, Peg: pegylated, tiw: three times weekly, ETR: undetectable HCV RNA at the end of treatment, SVR: sustained virological, HAI: Histological Activity Index ; nd: not defined, ns: not statistically significant.

			Transplantation
		Study	treatment interval	Antiviral therapy, time	N Genotype 1	Discontinuation (n)	ETR	SVR	Histological results	Adverse events
			(months)
	IFN vs Ribavirin monotherapy	Gane et al Hepatology 1998	> 6	IFN 3 MU tiw vs Ribavirin for 12 weeks	30	47%	2 in ribavirin group	IFN group: 46% Rib group: 17% p=ns	0	Reduction of inflammation: 21% in IFN group vs 64% in Rib group, p=0.05 No improvement of fibrosis	anemia leukopenia
		Cotler et al Transplantation 2001	> 7	IFN (3MU/day) vs no treatment for 48 weeks	12	33%	2 discontinuation in IFN group	IFN group: 4 (50%) Control group: 0	IFN: 1 (12,5%) Control group: 0	improvement in HAI score in the treated group p=0.04	Asthenia Depression
	Chalasani et al Hepatology 2005 Angelico et al J Hepatol 2007 Kizikisik et al Transpl Proc 1997 Ghalib et al Hepatol 2000 Samuel et al Gastroenterology 2003 Carrion et al Gastroenterology 2007 Abbreviations: N: number IFN IFN monotherapy vs bitherapy Bitherapy with Peg-IFN monotherapy Bitherapy with IFN	< 60 < 12 nd > 5 > 48 > 6 F o r Peg-IFN (1,5µg/kg/week) + Ribavirin Peg-IFN 180µg/week vs no treatment for 48 weeks Peg-IFN (180µg/week) vs Peg-IFN + Ribavirin for 48 weeks Ribavirin +/-IFN (3MU tiw) vs no treatment for 12 weeks IFN (6MU tiw) + Ribavirin for 24weeks vs 48 weeks IFN (3 MU tiw) + Ribavirin vs no treatment for 48 weeks vs no treatment for 48 weeks P e e r R e 67 42 19 10 52 81 v i 77% 83% nd 80% 83% 90% e	10 (30%) in treated group Withdrawals: Monotherapy: 6/21 Bitherapy: 7/21 Dose reductions: Monotherapy: 7 Bitherapy: 8 1 (17%) in treated group 5 completed treatment 12/28 (43%) in treated group Treatment interrumptions 39% Dose reductions 49/54	IFN group : 9 (27%) Control group: 0 Monotherapy: 76 Bitherapy: 71 0 in each group 24 weeks group: 3/3 48 weeks group: 1/2 Treated group: 32% Control group: 0 p=.02 nd	IFN group: 4 (12%) Control group: 0 Monotherapy: 38 Bitherapy: 33 0 in each group 24 weeks group: 1/3 48 weeks group: 1/2 Treated group: 21% Control group: 0 p=.04 Treated group: 18 (33%) Control group: 0	HAI score and fibrosis lower in the treated group but not significant Improvement necro-inflammatory score: Monotherapy: 7/11(64) Bitherapy: 2/10(20) Improvement fibrosis score: Monotherapy: 5/11(45) Bitherapy: 2/10(20) nd nd No significant histologic improvement Liver fibrosis progressed >1 stage in 70% of control group versus 39% of treated group p<0.01	Flu like sypmtoms Headache Asthenia Thrombocytopenia Hemolytic anemia nd Flu like sypmtoms mild fatigue Anemia Psychiatric disorders 1 chronic rejection Anemia Asthenia, fever
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Alimentary Pharmacology & Therapeutic

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Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

Synthesis of results

14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2 ) for each meta-analysis.


Marco Scioscia

Mariangela Fornalè

Francesco Bruni

Daniela Peretti

Keywords: Umbilical cord knot, ultrasound, clinical management, Doppler velocimetry

4D and Doppler sonography in the diagnosis and surveillance of a true cord knot

Clinical evidence at birth of true knots of the umbilical cord is not uncommon, with a reported incidence of about 1% of all deliveries 1 , and is associated with an estimated risk of antepartum fetal demise up to ten times higher than in the general population 2 .

Most true knots present as an unexpected finding at delivery and are not associated to an increased risk of obstetrical intervention and poor neonatal outcomes 2 as the larger part of these are loose knots.

On the other hand, the loose knot may tighten during pregnancy for active fetal movements or during labor leading to fetal distress or asphyxia till intrauterine death.

Prenatal diagnosis of a true knot of the umbilical cord is very often an incidental observation at ultrasound and very little is known about the optimal management of these cases. We report a case of sonographic evidence of a true knot of the umbilical cord and the relevance of ultrasound in its longitudinal management. A 44-year-old, gravida 4 para 2, was referred to our unit at 28 weeks of gestation for a routine ultrasound scan. During the examination, a double loop floating loosely in the amniotic fluid was seen on a longitudinal section of the umbilical cord (Figure 1A) which was confirmed on color flow imaging as being cord vessels (Figure 1C), thus the suspect of a cord knot was made. To differentiate between true and false knots, we looked for the "four-leaf clover" image and the "hanging nose" sign 3 , two reported sonographic characteristics of true knots, but they were not obtained on any section plane. We further assessed the putative knot using fourdimensional ultrasound (Xario, Toshiba, Japan) that confirmed the presence of a loose true knot (Figure 1D). Subsequently, umbilical artery Doppler was assessed before and after the knot (resistance index 0.62 and 0.77, respectively; Figure 2A-B). A specific counseling was made and was proposed another sonographic evaluation in a week to confirm the presence of the knot and to repeat the Doppler assessment (because of the slightly increase in resistances after the knot). At 29 weeks, the same imagine was recorded with no differences in resistance indexes between proximal and distal to the knot (0.66 vs 0.68). The patient was fully aware of the situation and accepted to carry on the pregnancy with a close The patient was instructed to report the sonographic suspect to the midwife upon admission to hospital in case of spontaneous onset of labor and was aware that an emergency caesarean section could have been performed in case of instrumental (sonographic or cardiotocographic) evidence of fetal distress. All sonographic evaluations showed the same image (Figure 1B) and good Doppler assessment (Figure 2C-D) until term (last evaluation at 37w 5d with RI of 0.48 and 0.47 proximal and distal to the knot, respectively) when she was admitted at 39 weeks of gestation for spontaneous onset of labor. No alterations were recorded at cardiotocography (only sporadic early decelerations) and a male neonate of 3850 grams born with a 10/10 Apgar scores and normal arterial pH in the umbilical cord. The presence of a loose true knot was confirmed at birth. Notwithstanding the relatively high incidence of true knots of the umbilical cord at birth and the increased risk of stillbirth 2,4 , a prenatal diagnosis is infrequently reported 3 . Different sonographic characteristics have been proposed as typical images to identify true knots although none of them has been reported to be specific for the diagnosis 5 . Indeed, it is a difficult diagnosis but supplementary ultrasonographic evaluations including color Doppler imaging, Doppler flow velocimetry and four-dimensional ultrasound may improve the detection rate of true knots and differentiate these from false images (false knots). In our case the differential diagnosis was possible using the 4D imaging that clearly showed a true knot with further information that it was a loose one.

Once the prenatal diagnosis of a true knot is highly suspected, the management of the case has to be prudent, given the increased risk of intrauterine fetal demise 1,2 , and an adequate counseling has to be offered to parents. A longitudinal assessment has to be planned to monitor the pregnancy, mainly based on umbilical artery Doppler velocimetry till term and cardiotocography in continuum during labor is recommended.

In conclusion, four-dimensional ultrasound helps for the differential diagnosis in case of suspect of cord knot and the Doppler

Figure 1b

Bi-dimensional images of the cord knot later in pregnancy (32 weeds). The 2D spatial arrangement of the loops appears strongly suggestive of a knot in this section.

Figure 1c

Longitudinal section of the cord at 28 weeks of gestation on color Doppler. Doppler sonography displayed a vascular spatial configuration pattern consistent with a true knot of the umbilical cord in all of the planes.

Figure 1d

Longitudinal section of the cord at 28 weeks of gestation on fourdimensional ultrasonography. Three-dimensional is helpful in

Figure 2a

Doppler flow velocimetry of the umbilical artery proximal to the knot at 28 weeks of gestation.

Figure 2b

Doppler flow velocimetry of the umbilical artery distal to the knot at 28 weeks of gestation. The assessment of differences in resistance indexes suggests a tightening knot.

Figure 2c

Doppler flow velocimetry of the umbilical artery proximal to the knot at 32 weeks of gestation.

Figure 2d

Doppler flow velocimetry of the umbilical artery distal to the knot at 32 weeks of gestation. Clinical evidence at birth of true knots of the umbilical cord is not uncommon, with a reported incidence of about 1% of all deliveries 1 , and is associated with an estimated risk of antepartum fetal demise up to ten times higher than in the general population 2 .

Most true knots present as an unexpected finding at delivery and are not associated to an increased risk of obstetrical intervention and poor neonatal outcomes 2 as the larger part of these are loose knots.

On the other hand, the loose knot may tighten during pregnancy for active fetal movements or during labor leading to fetal distress or asphyxia till intrauterine death.

Prenatal diagnosis of a true knot of the umbilical cord is very often an incidental observation at ultrasound and very little is known about the optimal management of these cases. We report a case of sonographic evidence of a true knot of the umbilical cord and the relevance of ultrasound in its longitudinal management. A 44-year-old, gravida 4 para 2, was referred to our unit at 28 weeks of gestation for a routine ultrasound scan. During the examination, a double loop floating loosely in the amniotic fluid was seen on a longitudinal section of the umbilical cord (Figure 1A) which was confirmed on color flow imaging as being cord vessels (Figure 1C), thus the suspect of a cord knot was made. To differentiate between true and false knots, we looked for the "four-leaf clover" image and the "hanging nose" sign 3 , two reported sonographic characteristics of true knots, but they were not obtained on any section plane. We further assessed the putative knot using fourdimensional ultrasound (Xario, Toshiba, Japan) that confirmed the presence of a loose true knot (Figure 1D). Subsequently, umbilical artery Doppler was assessed before and after the knot (resistance index 0.62 and 0.77, respectively; Figure 2A-B). A specific counseling was made and was proposed another sonographic evaluation in a week to confirm the presence of the knot and to repeat the Doppler assessment (because of the slightly increase in resistances after the knot). At 29 weeks, the same imagine was recorded with no differences in resistance indexes between proximal and distal to the knot (0.66 vs 0.68). The patient was fully aware of the situation and accepted to carry on the pregnancy with a close Notwithstanding the relatively high incidence of true knots of the umbilical cord at birth and the increased risk of stillbirth 2,4 , a prenatal diagnosis is infrequently reported 3 . Different sonographic characteristics have been proposed as typical images to identify true knots although none of them has been reported to be specific for the diagnosis 5 . Indeed, it is a difficult diagnosis but supplementary ultrasonographic evaluations including color Doppler imaging, Doppler flow velocimetry and four-dimensional ultrasound may improve the detection rate of true knots and differentiate these from false images (false knots). In our case the differential diagnosis was possible using the 4D imaging that clearly showed a true knot with further information that it was a loose one.

Once the prenatal diagnosis of a true knot is highly suspected, the management of the case has to be prudent, given the increased risk of intrauterine fetal demise 1,2 , and an adequate counseling has to be offered to parents. A longitudinal assessment has to be planned to monitor the pregnancy, mainly based on umbilical artery Doppler velocimetry till term and cardiotocography in continuum during labor is recommended.

In conclusion, four-dimensional ultrasound helps for the differential diagnosis in case of suspect of cord knot and the Doppler

Figure 1b

Bi-dimensional images of the cord knot later in pregnancy (32 weeds). The 2D spatial arrangement of the loops appears strongly suggestive of a knot in this section.

Figure 1c

Longitudinal section of the cord at 28 weeks of gestation on color Doppler. Doppler sonography displayed a vascular spatial configuration pattern consistent with a true knot of the umbilical cord in all of the planes.

Figure 1d

Longitudinal section of the cord at 28 weeks of gestation on fourdimensional ultrasonography. Three-dimensional is helpful in

Figure 2a

Doppler flow velocimetry of the umbilical artery proximal to the knot at 28 weeks of gestation.

Figure 2b

Doppler flow velocimetry of the umbilical artery distal to the knot at 28 weeks of gestation. The assessment of differences in resistance indexes suggests a tightening knot.

Figure 2c

Doppler flow velocimetry of the umbilical artery proximal to the knot at 32 weeks of gestation.

Figure 2d

Doppler flow velocimetry of the umbilical artery distal to the knot at 32 weeks of gestation.

  daily fetal movements (maternal subjective perception) and by fortnightly Doppler ultrasonography.

  Figure legends

  the presence of a true knot of the umbilical cord mainly in the second trimester when it "floats" in a pocket of amniotic fluid.

  daily fetal movements (maternal subjective perception) and by fortnightly Doppler ultrasonography.The patient was instructed to report the sonographic suspect to the midwife upon admission to hospital in case of spontaneous onset of labor and was aware that an emergency caesarean section could have been performed in case of instrumental (sonographic or cardiotocographic) evidence of fetal distress. All sonographic evaluations showed the same image (Figure1B) and good Doppler assessment (Figure2C-D) until term (last evaluation at 37w 5d with RI of 0.48 and 0.47 proximal and distal to the knot, respectively) when she was admitted at 39 weeks of gestation for spontaneous onset of labor. No alterations were recorded at cardiotocography (only sporadic early decelerations) and a male neonate of 3850 grams born with a 10/10 Apgar scores and normal arterial pH in the umbilical cord. The presence of a loose true knot was confirmed at birth.

  a useful tool to assist in the diagnosis of a true knot that is found to be initially loose and may tighten for active fetal movements throughout the pregnancy.

  Figure legends

  of a true knot of the umbilical cord mainly in the second trimester when it "floats" in a pocket of amniotic fluid.

  Fig 1a Bi-dimensional images of the cord knot at diagnosis (28 weeks). Doppler sonography displayed a vascular spatial configuration pattern consistent with a true knot of the umbilical cord in all of the planes. 269x192mm (96 x 96 DPI)

John Wiley & SonsJournal of Clinical Ultrasound

John Wiley & Sons

Journal of Clinical Ultrasound


David Rafael Hartge

Roland Axt-Fliedner

Jan Weichert

Keywords: choroid plexus papilloma, fetus, CNS, embolisation, ultrasound fetus, CNS, choroid plexus papilloma, ultrasound, embolisation, craniotomy 13 14

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Prenatal diagnosis and successfull postnatal therapy of an atypical choroid plexus papilloma -Case report and review of literature

to the fact that CPP is only representing approximately 3-10% of all pediatric 10 tumors of the central nervous system (1, 2, 3) large studies do not exist. This 11 causes a lack of valid recommendations for therapeutical management regarding 12 CPP and similar benign intracranial tumors of the fetus and the neonate. 13

This case report depicts a feasable perinatal management and successfull postoperative 14 diagnostic and therapeutic regimen in an otherwise healthy child with an ultrasound-detected 15 lesion suspicious for a CPP. A review of literature including related papers listed in Pubmed 16 between 1985-2009 was added to this report. Case Report: 1 Presentation of a 29 years old women, IG 0P, BMI 26,7, no regular medication, no 2 chronic diseases, no former surgical interventions, with an intact, non-3 consanguineous singleton pregnancy in the 31st week of gestation: A targeted 4 ultrasound scan (HDI 5000, Phillips Healthcare, Andover, Mass., USA; Voluson 5 730 Pro, GE Healthcare, Chalfont-St.-Giles, England; 2-5 MHz trans-abdominal 6 probes) revealed an echogenic, slightly perfused mass of about 1 cm in diameter 7 within the posterior horn of the right lateral fetal ventricle and a moderate ipsilateral 8 ventriculomegaly without any additional anomalies (Figure 1-3). There were no 9 signs of invasive growth. Fetal blood sampling revealed normal blood values and a 10 normal female karyotype (46 XX). Serial follow-up scans were scheduled every 14 11 days and showed a marked increase in tumor size: Within two weeks the lesion 12 having now 6 cm of diameter caused a midline deviation of the cerebral structures 13 and a beginning macrocephaly (Figure 4). Color Doppler and Power Doppler 14 mapping (Figure 5) confirmed increasing vascularization within the tumor with low 15 pulsatility indices. These findings were highly suggestive of a choroid plexus tumor 16 and elective caesarean section without intricacies was performed at completed 17 35th week of gestation. Confirming the prenatal data the newborn, an otherwise 18 healthy girl, APGAR 7/8/10, length 48 cm, 2230g, UApH: 7.29, had a macrocephaly 19 and a diastasis of the sagittal cranial suture. A cranial MRI and a MR-angiography 20 of the neonate on the first day of life revealed a contrast enhancing tumor in the 21 lateral right ventricle of 8 cm in diameter (Figure 6). The tumor was supplied by the 22 posterior choroid artery approximately 1 mm in diameter. At the sixth day of life an 23 elective conventional angiography confirmed the posterior choroid artery as feeding 1 vessel of the tumor. There were no signs of arterio-venous shunts or additional 2 blood supply by other vessels. Consecutive coiling of the associated artery with 3 3 GDC-Coils and 3 Liquid-Coils lead to a negative blushing of the tumor in the post-4 procedure angiogram (Figure 7a and7b). One day after the successfull 5 embolization of the feeding vessel a right temporal craniotomy with 3cm 6 corticotomy was perfomed. The tumor was removed entirely in a complication-free 7 intervention (Figure 8). Only an external ventricular drainage was necessary for 3 8 days following operation. 9

Histological and immunohistochemical examination revealed a highly differentiated choroid 10 plexus tumor without nuclear atypia or necrosis and excluded other origins. The tumor 11 showed an increased rate of mitotic activity. Therefore CPP was classified WHO Grade II. 12 One, two and three year follow-up showed a normal neuromotoric development of the child. 13 14

Discussion: 15

CPPs are benign tumors. CPP originates from the neuroepithelial cells of the 16 choroid plexus. The plexus is located in the body and inferior horn of the lateral 17 ventricles, in the interventricular foramen and in the third and fourth ventricle. CPPs 18 can therefore be found in all these locations described above. In pediatric patients 19 CPPs are found in the lateral ventricle with 71% of all cases (2,4,5). CPP growth 20 in the third and forth ventricle are rare (6,7,8). In adults the alocation of CPP is 21 sligthly different: main region of initial growth of CPPs is the fourth ventricle (76%) 22 as it was shown in a single center population with a median age of 36 years (9). 23 Extraventricular occurrence of CPPs is an exception (10). Bilateral ventricular 1 growth has been regularly reported (11,12). CPPs are described as tumors 2 showing a non-invasive and slow growth (12) but due to their specific localization 3 they are accidentally occluding the liqour drainage and causing an internal 4 hydrocephalus. The situation may be aggravated by the potential ability of a CPP 5 producing cerebrospinal fluid (CSF) itself. 6

In our case we saw an unusually rapid tumor expansion from 1 to 8 cm in 7 approximately 6 weeks. 8

Table 1 shows previous studies regarding CPP. 9 10

In adults CPPs account for less than 1% of all brain tumors (13). In contrast 3-10% 11 of all pediatric tumors of the central nervous system are choroid plexus papillomas 12

(1, 2, 3). The median age of children at time of diagnosis is 22.5 months. One-half 13 of the patients are reported to be younger than 2 years when CPP becomes 14 evident (4). This is one of the rare cases where CPP was suspected prenatally. 15 16 CPP is a polygenetic disorder (14). Different genetic loci have been described to be 17 following alterations have been reported in CPP (18): +7q (65%), +5q (62%), +7p 1 (59%), +5p (56%), +9p (50%), +9q (41%), +12p, +12q (38%), +8q (35%), -10q 2 (56%), -10p, and -22q (47%). CPPs in childhood show different chromosomal 3 alterations with +8q, +14q, +12, and +20q suggesting a different genetic pathway. 4

A duplication of 9p has been shown in few cases of choroid plexus carcinoma and 5

CPP as well. 6

In our case no chromosomal imbalances could be detected. 7

There are two syndromes known which are considered to coincide with CPP: 8

Aicardi-Goutiéres-Syndrome (AGS) (12) and Hypomelanosis of Ito (HI) (14). Both 9 syndromes are associated with other significant problems. Patients with AGS, a 10 multigenetic disorder with similarities to characteristic features of congenital 11 infections, have malformations of the brain, like agenesis of corpus callosum and a 12 considerable developmental impairment (12,19,20). HI is described as an 13 accumulation of neurological and skeletal anomalies. Its name originates from the 14 characteristic small hypopigmented macules on the skin along the lines of 15 Blaschko of the affected individuals. In combination with the chromosomal 16 translocation X;17(q12;p13) HI has been found with CPP (21,22). 17

The child in our case did not show any signs of these specific features. 18

Another factor in the development of a CPP may be seen in intrauterine infections. 19

There is evidence of similarities between DNA found in choroid plexus tumors and 20 enpendymomas and those of simian virus 40 (23) Two case-reports implicating connections between the presentation of Hippel-1 Lindau-disease, a genetic disorder located on chromosome 3 p25/26 and 2 characterised by haemangiomas and/or haemangioblastomas situated in the brain 3 stem, cerebellum, spinal cord or retina. CPP or invasive choroid plexus tumor 4 respectively having been seen coexisting in the same individual with Hippel-Lindau 5 disease in adulthood (25,26) The most common clinical signs of children with CPP are provoced by raised 1 intracranial pressure caused by increasing hydrocephalus (6). Children may suffer 2 from headaches, nausea and vomiting, focal neurological deficits, macrocephaly 3 and epileptic seizures (5). Hydrocephalus is evident in approximately 85-87% of all 4 cases (4, 31). There seems to be no prognostic impact in occurrence of 5 hydrocephalus. It correlates poorly with the actual size and pathological features of 6 the tumor (4). 7 8 Diagnostic procedures/imaging of CPP are normally performed after first symptoms 9 have been noted in an affected individual. MRI displays CPP as a lobulated 10 contrast-enhancing lesion similar to grey matter on T1w images often accompanied 11 by an enlarged lateral ventricle. T2w imaging presents a hyperintense lesion (1, 12 32). Computed tomography shows an isodense to hyperdense lesion often 13 presenting intra-tumoral calcifications with uniform contrast enhancement (6, 28, 14 30). CPP in transabdominal ultrasound imaging of an affected fetus shows an 15 echogenic, lobulated intraventricular tumor typically associated with feeding 16 vessel(s) in color flow Doppler mapping. Adding the sonographic presentation of 17 hydrocephalus the triad postulated for CPP by Adra et al.,1994, (6) is completed. 18 In our case we report on an echogenic intraventricular tumor with ipsilateral 19 ventriculomegaly (Figure 1-3). This tumor showed an significant tumor growth 20 causing a midline deviation of the cerebral structures and a macrocephaly as well 21 (Figure 4). At the end of pregnancy nearly the complete ipsilateral cerebral 22 hemisphere was displaced by the tumor. Color Doppler and Power Doppler 23 mapping (Figure 5) confirmed increasing vascularization within the tumor with low 1 pulsatility indices. In some areas of this lobulated tumor we also could detect minor 2

calcifications. 3

We were able to confirm the triad postulated by Adra et al., 1994. 4 5 Complete surgical excision of the tumor tissue is considered to be the treatment of 6 choice for CPPs (4, 9). Surgical intervention is complicated by a risk of 7 intraoperative hemorrhage which is a common and often lethal emergency in 8 resection of CPPs (4,11). In about 15% of CPPs being operated a gross total 9 resection (GTR) could not be achieved due to vascular problems (5, 9). Significant 10 blood-loss may be prevented by preoperative embolisation (33). Even partial 11 embolisation may decrease the severity of intraoperative hemorrhage. 12

In 24-41% of reported cases a ventriculo-peritoneal shunt was necessary (4, 31). 13

Preoperative symptoms have proved to be an independent marker for the need of 14 ventriculo-peritoneal shunting after surgery took place (4). In our case the patient 15 needed an external ventricular drainage for 3 days after the intervention. 16

Postoperative brain collapse causing subdural fluid collections may occur and 17 require a subduro-peritoneal shunting drainage in 8-14% of cases (4, 31). 18

Therefore preoperative controlled drainage of the affected ventricle and 19 intraoperative anchorage adjacent to the cortical incision are recommended by 20 some authors (4). In our case we did not seal the temporal corticotomy by using a 21 biological glue. After the procedure moderate subdural hygroma developed 22 postoperatively and resolved spontaneously. In 22% of cases temporary swallowing dysfunction has been described as an 1 noteable postoperative complication with frequent need for tracheostomy or 2 percutan gastrostomy (9). 3

Adding chemo-and/or radiation-therapy does not significantly influence the overall 4 suvival rate. Adequate therapy in case of recurrence of symptoms where a subtotal 5 resection (STR) of the tumor had been performed seems to be the re-operation ( 5), 6

which is reported to be necessary in about 50% of such cases (9). Radiation may 7 be an alternative option in the rare constellation of STR after recurrence of a CPP 8 (9) and in cases where a surgical intervention is not feasible (34). 9 10 CNS neoplasms are responsible for 5-20% of deaths in the fetal or neonatal period 11

(1). The prognosis of CPP is favourable for patients treated with GTR. Malignant 12 transformation is described in pediatric patients with STR but seems to be a very 13 rare incident (5,30,35). The overall 5-year survival rate in cases with GTR is 14 reported with 100% (4). In our case the outcome of the otherwise healthy girl was 15 good. Complete neuro-pediatric status was performed and no signs of neurological 16 impairment could be found. Physical development was also regular. Follow-up was 17 three years. 18 19

Conclusion: 20

This is the first reported case of an atypical CPP being diagnosed prenatally and 21 successfully embolised and resected postnatally with a favourable outcome of the 22 affected child. This report shows that it is feasible to detect tumors like CPP 23

Abstract: 1

This report shows the perinatal management of a prenatally detected choroid 2 plexus papilloma (CPP) in an otherwise unaltered singleton pregnancy of an 3 healthy women. After elective caesarian section a sucessfull embolisation of the 4 feeding vessel followed by a craniotomy and complete removal of the remaining 5 tumor was performed. Histological examination confirmed CPP WHO Grade II. 6

One, two and three year follow-up showed a normal development of the girl with a regular 7 neuro-pediatric status. elective conventional angiography confirmed the posterior choroid artery as feeding 1 vessel of the tumor. There were no signs of arterio-venous shunts or additional 2 blood supply by other vessels. Consecutive coiling of the associated artery with 3 3 GDC-Coils and 3 Liquid-Coils lead to a negative blushing of the tumor in the post-4 procedure angiogram (Figure 7a and7b). One day after the successfull 5 embolization of the feeding vessel a right temporal craniotomy with 3cm 6 corticotomy was perfomed. The tumor was removed entirely in a complication-free 7 intervention (Figure 8). Only an external ventricular drainage was necessary for 3 8 days following operation. 9

Histological and immunohistochemical examination revealed a highly differentiated choroid 10 plexus tumor without nuclear atypia or necrosis and excluded other origins. The tumor 11 showed an increased rate of mitotic activity. Therefore CPP was classified WHO Grade II. 12 One, two and three year follow-up showed a normal neuromotoric development of the child. 13 14

Discussion: 15

CPPs are benign tumors. CPP originates from the neuroepithelial cells of the 16 choroid plexus. The plexus is located in the body and inferior horn of the lateral 17 ventricles, in the interventricular foramen and in the third and fourth ventricle. CPPs 18 can therefore be found in all these locations described above. In pediatric patients 19 CPPs are found in the lateral ventricle with 71% of all cases (2, 4, 5). CPP growth 20 in the third and forth ventricle are rare (6, 7, 8). In adults the alocation of CPP is 21 sligthly different: main region of initial growth of CPPs is the fourth ventricle (76%) 22 as it was shown in a single center population with a median age of 36 years (9). 23 Extraventricular occurrence of CPPs is an exception (10). Bilateral ventricular 1 growth has been regularly reported (11,12). CPPs are described as tumors 2 showing a non-invasive and slow growth (12) but due to their specific localization 3 they are accidentally occluding the liqour drainage and causing an internal 4 hydrocephalus. The situation may be aggravated by the potential ability of a CPP 5 producing cerebrospinal fluid (CSF) itself. 6

In our case we saw an unusually rapid tumor expansion from 1 to 8 cm in 7 approximately 6 weeks. 8

Table 1 shows previous studies regarding CPP. 9 10 In adults CPPs account for less than 1% of all brain tumors (13). In contrast 3-10% 11 of all pediatric tumors of the central nervous system are choroid plexus papillomas 12

(1, 2, 3). The median age of children at time of diagnosis is 22.5 months. One-half 13 of the patients are reported to be younger than 2 years when CPP becomes 14 evident (4). This is one of the rare cases where CPP was suspected prenatally. 15 16 CPP is a polygenetic disorder (14). Different genetic loci have been described to be 17 following alterations have been reported in CPP (18): +7q (65%), +5q (62%), +7p 1 (59%), +5p (56%), +9p (50%), +9q (41%), +12p, +12q (38%), +8q (35%), -10q 2 (56%), -10p, and -22q (47%). CPPs in childhood show different chromosomal 3 alterations with +8q, +14q, +12, and +20q suggesting a different genetic pathway. 4

A duplication of 9p has been shown in few cases of choroid plexus carcinoma and 5

CPP as well. 6

In our case no chromosomal imbalances could be detected. 7

There are two syndromes known which are considered to coincide with CPP: 8

Aicardi-Goutiéres-Syndrome (AGS) ( 12) and Hypomelanosis of Ito (HI) ( 14). Both 9 syndromes are associated with other significant problems. Patients with AGS, a 10 multigenetic disorder with similarities to characteristic features of congenital 11 infections, have malformations of the brain, like agenesis of corpus callosum and a 12 considerable developmental impairment (12,19,20). HI is described as an 13 accumulation of neurological and skeletal anomalies. Its name originates from the 14 characteristic small hypopigmented macules on the skin along the lines of 15 Blaschko of the affected individuals. In combination with the chromosomal 16 translocation X;17(q12;p13) HI has been found with CPP (21,22). 17

The child in our case did not show any signs of these specific features. 18

Another factor in the development of a CPP may be seen in intrauterine infections. 19

There is evidence of similarities between DNA found in choroid plexus tumors and 20 The most common clinical signs of children with CPP are provoced by raised 1 intracranial pressure caused by increasing hydrocephalus (6). Children may suffer 2 from headaches, nausea and vomiting, focal neurological deficits, macrocephaly 3 and epileptic seizures (5). Hydrocephalus is evident in approximately 85-87% of all 4 cases (4, 31). There seems to be no prognostic impact in occurrence of 5 hydrocephalus. It correlates poorly with the actual size and pathological features of 6 the tumor (4). 7 8 Diagnostic procedures/imaging of CPP are normally performed after first symptoms 9 have been noted in an affected individual. MRI displays CPP as a lobulated 10 contrast-enhancing lesion similar to grey matter on T1w images often accompanied 11 by an enlarged lateral ventricle. T2w imaging presents a hyperintense lesion (1, 12 32). Computed tomography shows an isodense to hyperdense lesion often 13 presenting intra-tumoral calcifications with uniform contrast enhancement (6, 28, 14 30). CPP in transabdominal ultrasound imaging of an affected fetus shows an 15 echogenic, lobulated intraventricular tumor typically associated with feeding 16 vessel(s) in color flow Doppler mapping. Adding the sonographic presentation of 17 hydrocephalus the triad postulated for CPP by Adra et al.,1994, ( 6) is completed. 18

In our case we report on an echogenic intraventricular tumor with ipsilateral 19 ventriculomegaly (Figure 1-3). This tumor showed an significant tumor growth 20 causing a midline deviation of the cerebral structures and a macrocephaly as well 21 (Figure 4). At the end of pregnancy nearly the complete ipsilateral cerebral 22 hemisphere was displaced by the tumor. Color Doppler and Power Doppler 23 mapping (Figure 5) confirmed increasing vascularization within the tumor with low 1 pulsatility indices. In some areas of this lobulated tumor we also could detect minor 2

calcifications. 3

We were able to confirm the triad postulated by Adra et al., 1994. 4 5 Complete surgical excision of the tumor tissue is considered to be the treatment of 6 choice for CPPs (4, 9). Surgical intervention is complicated by a risk of 7 intraoperative hemorrhage which is a common and often lethal emergency in 8 resection of CPPs (4,11). In about 15% of CPPs being operated a gross total 9 resection (GTR) could not be achieved due to vascular problems (5, 9). Significant 10 blood-loss may be prevented by preoperative embolisation (33). Even partial 11 embolisation may decrease the severity of intraoperative hemorrhage. 12

In 24-41% of reported cases a ventriculo-peritoneal shunt was necessary (4, 31). 13

Preoperative symptoms have proved to be an independent marker for the need of 14 ventriculo-peritoneal shunting after surgery took place (4). In our case the patient 15 needed an external ventricular drainage for 3 days after the intervention. 16

Postoperative brain collapse causing subdural fluid collections may occur and 17 require a subduro-peritoneal shunting drainage in 8-14% of cases (4, 31). 18

Therefore preoperative controlled drainage of the affected ventricle and 19 intraoperative anchorage adjacent to the cortical incision are recommended by 20 some authors (4). In our case we did not seal the temporal corticotomy by using a 21 biological glue. After the procedure moderate subdural hygroma developed 22 postoperatively and resolved spontaneously. In 22% of cases temporary swallowing dysfunction has been described as an 1 noteable postoperative complication with frequent need for tracheostomy or 2 percutan gastrostomy (9). 3

Adding chemo-and/or radiation-therapy does not significantly influence the overall 4 suvival rate. Adequate therapy in case of recurrence of symptoms where a subtotal 5 resection (STR) of the tumor had been performed seems to be the re-operation (5), 6

which is reported to be necessary in about 50% of such cases (9). Radiation may 7 be an alternative option in the rare constellation of STR after recurrence of a CPP 8 (9) and in cases where a surgical intervention is not feasible (34). 9 10 CNS neoplasms are responsible for 5-20% of deaths in the fetal or neonatal period 11

(1). The prognosis of CPP is favourable for patients treated with GTR. Malignant 12 transformation is described in pediatric patients with STR but seems to be a very 13 rare incident (5,30,35). The overall 5-year survival rate in cases with GTR is 14 reported with 100% (4). In our case the outcome of the otherwise healthy girl was 15 good. Complete neuro-pediatric status was performed and no signs of neurological 16 impairment could be found. Physical development was also regular. Follow-up was 17 three years. 18 19

Conclusion: 20

This is the first reported case of an atypical CPP being diagnosed prenatally and 21 successfully embolised and resected postnatally with a favourable outcome of the 22 affected child. This report shows that it is feasible to detect tumors like CPP 23

  Choroid plexus papilloma (CPP) is a rare benign intracranial tumor. Affected 2 children typically become conspicuous during their first 24 months showing signs of 3 increased intracranial pressure frequently suffering from headache, nausea and 4 vomiting, focal neurological impairments and convulsions. The slow growing CPP 5 may occlude the physiological drainage of the cerebrospinal fluid (CSF), and 6 additionally secretes CSF itself, provoking a clinical manifestation. Prenatal 7 detection of a hydrocephalus combined with an intraventricular tumor showing a 8 hypervascularisation without infiltrative growth pattern is suggestive of a CPP. Due 9

  possibly connected to the development of this benign tumor. Known associations 18 are mutations of the TP53 tumor supression gene (17p13.1) shown in germline 19 cells of an adult with CPP and also osteosarkoma (15). However, disregulation of 20 protein p53 is far more often present in cases with choroid plexus carcinoma than 21 in CPPs (16). Alterations in the hSNF5/INI1 gene (22q11.2) considered important 22 in choroid plexus carcinomas do not seem to have this impact on CPP (17). The 23

  23

  scans. A prenatal detection may lead to a proper 1 counselling of the parents and perinatal management improving the short-and 2 intermediate-term outcome of children with CPP or similar benign intracranial 3 MI, Weil-Lara B, Herrero-Hernández A: Papilloma and carcinoma 6 of the choroid plexus in pediatric patients [in spanish]. Radiologia 49: 279Sainte-Rose C, Lellouch-Tubiana A et al.: Papillomas and carcinomas 9 of the choroid plexus in children. J Neurosurg 88: 521-8, 1998 10 5 Chow E, Reardon DA, Shah AB et al.: Pediatric choroid plexus neoplasms. Int J 11 Radiat Oncol Biol Phys 44: 249-54, 1999 12 6 Adra A, Mejides AA, Salman FA et al.: Prenatal sonographic 13 diagnosis of a third ventricle choroid plexus papilloma. Prenatal Diagnosis, Shiokawa Y, Kobayashi K et al.: Choroid plexus papilloma of the 16 third ventricle in the fetus. Case illustration. J Neurosurg 100: 224Onuma T, Kameyama M et al.: Hydrocephalus due to cerebrospinal 1 fluid overproduction by bilateral choroid plexus papillomas. Childs Nerv Syst 20Polling JS, Ma LCK: Choroid plexus papilloma expansion over 7 years 4 in Aicardi syndrome. J Child Neurol 22: 484-7, 2007 5 13 Hamack JE: Choroid plexus papilloma and carcinoma (Chapter 26). In Raghavan 6 D, Brecher ML, Johnson DH et al.: Textbook of Uncommon Cancer, 2nd edition, 7 John Wiley & Sons, Chichester: 335-40, 1999 8 14 Kamaly-Asl ID, Shams N, Taylor MD: Genetics of choroid plexus tumors. 9 Neurosurg Focus 20: E10, 2006 10 15 Rutherford J, Chu CE, Duddy PM et al.: Investigations on a clinically and 11 functionally unusual and novel germline p53 mutation. Br J Cancer 86: 1592-6., Salhia B, Weitzman S et al.: Evaluation of proliferative index and 14 cell cycle protein expression in choroid plexus tumors in children. Acta 15 Neuropathol 103: 1-10, 2002 16 17 Mueller W, Eum JH, Lass U et al.: No evidence of hSNF5/INI1 point mutations in 17 choroid plexus papilloma. Neuropathol Appl Neurobiol 30: 304-7, 2004 18 18 Rickert CH, Wiestler OD, Paulus W: Chromosomal imbalances in choroid plexus 19 tumors. Am J Pathol 160: 1105-13, 2002 20 19 Aicardi J: Aicardi syndrome. Brain Dev 27: 164-71, 2005 21 20 Jepps H, Seal S, Hattingh L et al.: The neonatal form of Aicardi-Goutiéres 22 syndrome masquerading as congenital infection. Early Hum Dev 84: 783-5, 2008 23 I, Roche C, Martinez-Bermejo A et al.: Hypomelanosis of 1 ITO. A study of 76 infantile cases. Brain Dev 20: 36-43,1998 2 22 Sybert VP, Pagon RA: Hypomelanosis of Ito in a girl with plexus papilloma and 3 translocation (X;17). Hum Genet 93: 227, 1994 4 23 Bergsagel DJ, Finegold MJ, Butel JS et al.: DNA sequences similar to those of 5 simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl 6 J Med 326: 988-93, 1992 7 24 Small JA, Blair DG, Showalter SD et al.: Analysis of a transgenic mouse 8 containing simian virus 40 and v-myc sequences. Mol Cell Biol 5: 642-8, 1985 9 25 Blamires TL, Friedmann I, Moffat DA: Von Hippel-Lindau disease associated 10 with an invasive choroid plexus tumour presenting as a middle ear mass. J 11 Laryngol Otol 106: 429-35, 1992 12 26 Blamires TL, Maher ER: Choroid plexus papilloma. A new presentation of von 13 Hippel-Lindau (VHL) disease. Eye 6: 90-2, 1992 14 27 Patanakar T, Prasad S, Mukherji SK et al.: Cystic variant of choroid plexus 15 papilloma. Clin Imaging 24: 130-1, 2000 16 28 Murata M, Morokuma S, Tsukimori K et al.: Rapid growing cystic variant of 17 choroid plexus papilloma in a fetal cerebral hemisphere. Ultrasound Obstet 18 Gynecol 33: 116-8, 2009 19 29 Brassesco MS, Valera ET, Neder L et al.: Polyploidy in atypical grade II choroid 20 plexus papilloma of the posterior fossa. Neuropathology, 29: 293-8, 2009 21 30 Coates TL, Hinshaw DB Jr, Peckman N et al.: Pediatric choroid plexus 22 neoplasms: MR, CT, and pathologic correlation. Radiology 173: 81-8, 1989 23 Harding BN, Phipps KP et al.: Managment of choroid plexus 1 tumors in children: 20 years experience at a single neurosurgical centre. Pediatr 2 Neurosurg 32: 192-9, 2000 3 32 Eren S, Polat P, Tüzün Y et al.: Ultrasound and Magnetic Resonance Imaging 4 Findings of Choroid plexus papilloma. Tr J Medical Sciences 29: 341-3, 1999 5 33 Otten ML, Riina HA, Gobin YP et al.: Preoperative embolization in the treatment 6 of choroid plexus papilloma in an infant. Case report. J Neurosurg 104: 429-21, 7 2006 8 34 Kim IY, Niranjan A, Kondziolka D et al.: Gamma knife radiosurgery for 9 treatment resistant choroid plexus papillomas. J Neurooncol 90: 105-10, 2008 10 35 Jeibmann A, Wrede B, Peters O, Wolff JE, Paulus W, Hasselblatt M: Malignant 11 progression in choroid plexus papillomas. J Neurosurg 107: 199-202

  8 A review of literature including related papers listed in Pubmed between 1985-2009 was 9 added to this report. Choroid plexus papilloma (CPP) is a rare benign intracranial tumor. Affected 2 children typically become conspicuous during their first 24 months showing signs of 3 increased intracranial pressure frequently suffering from headache, nausea and 4 vomiting, focal neurological impairments and convulsions. The slow growing CPP 5 may occlude the physiological drainage of the cerebrospinal fluid (CSF), and 6 additionally secretes CSF itself, provoking a clinical manifestation. Prenatal 7 detection of a hydrocephalus combined with an intraventricular tumor showing a 8 hypervascularisation without infiltrative growth pattern is suggestive of a CPP. Due 9to the fact that CPP is only representing approximately 3-10% of all pediatric 10 tumors of the central nervous system (1, 2, 3) large studies do not exist. This 11 causes a lack of valid recommendations for therapeutical management regarding 12 CPP and similar benign intracranial tumors of the fetus and the neonate. 13This case report depicts a feasable perinatal management and successfull postoperative 14 diagnostic and therapeutic regimen in an otherwise healthy child with an ultrasound-detected 15 lesion suspicious for a CPP. A review of literature including related papers listed in Pubmed 16 between 1985-2009 was added to this report.Presentation of a 29 years old women, IG 0P, BMI 26,7, no regular medication, no 2 chronic diseases, no former surgical interventions, with an intact, non-3 consanguineous singleton pregnancy in the 31st week of gestation: A targeted 4 ultrasound scan (HDI 5000, Phillips Healthcare, Andover, Mass., USA; Voluson 5 730 Pro, GE Healthcare, Chalfont-St.-Giles, England; 2-5 MHz trans-abdominal 6 probes) revealed an echogenic, slightly perfused mass of about 1 cm in diameter 7 within the posterior horn of the right lateral fetal ventricle and a moderate ipsilateral 8 ventriculomegaly without any additional anomalies (Figure1-3). There were no 9 signs of invasive growth. Fetal blood sampling revealed normal blood values and a 10 normal female karyotype (46 XX). Serial follow-up scans were scheduled every 14 11 days and showed a marked increase in tumor size: Within two weeks the lesion 12 having now 6 cm of diameter caused a midline deviation of the cerebral structures 13 and a beginning macrocephaly (Figure4). Color Doppler and Power Doppler 14 mapping (Figure5) confirmed increasing vascularization within the tumor with low 15 pulsatility indices. These findings were highly suggestive of a choroid plexus tumor 16 and elective caesarean section without intricacies was performed at completed 17 35th week of gestation. Confirming the prenatal data the newborn, an otherwise 18 healthy girl, APGAR 7/8/10, length 48 cm, 2230g, UApH: 7.29, had a macrocephaly 19 and a diastasis of the sagittal cranial suture. A cranial MRI and a MR-angiography 20 of the neonate on the first day of life revealed a contrast enhancing tumor in the 21 lateral right ventricle of 8 cm in diameter (Figure6). The tumor was supplied by the 22 posterior choroid artery approximately 1 mm in diameter. At the sixth day of life an 23

  possibly connected to the development of this benign tumor. Known associations 18 are mutations of the TP53 tumor supression gene (17p13.1) shown in germline 19 cells of an adult with CPP and also osteosarkoma (15). However, disregulation of 20 protein p53 is far more often present in cases with choroid plexus carcinoma than 21 in CPPs (16). Alterations in the hSNF5/INI1 gene (22q11.2) considered important 22 in choroid plexus carcinomas do not seem to have this impact on CPP (17). The 23

  enpendymomas and those of simian virus 40 (23). Secondary artificial choroid 21 plexus tumor growth as been induced experimenally by adding typical viral product, 22 T antigen, in transgenic mice (24). 23 Two case-reports implicating connections between the presentation of Hippel-1 Lindau-disease, a genetic disorder located on chromosome 3 p25/26 and 2 characterised by haemangiomas and/or haemangioblastomas situated in the brain 3 stem, cerebellum, spinal cord or retina. CPP or invasive choroid plexus tumor 4 respectively having been seen coexisting in the same individual with Hippel-Lindau 5 disease in adulthood (25, 26). 6 7 CPP-cells are similar to choroid-plexus-cells which are cuboidal epithelial cells 8 based on papillary fibrovascular tissue. This explains why CPP-cells are able to 9 produce CSF (11). CPP normally consists of highly differentiated cells without 10 signs of increased mitotic activity, nuclear atypia, necrotic areas and/or altered 11 vascularisation. Tumors consisting of these cells are classified as CPP WHO grade 12 I. Minor calcification of the fibrocascular stroma is not an uncommon sign. 13Expansion of cysts accompanying a CPP may be seen (27), deterioration of 14 cerebral tissue through cystic development is found sporadically (28). In our 15 discussed case we saw a higher mitotic activity, leading to a classification 16 analogous to WHO grade II. Due to the higher grading in our case the tumor has to 17 be labelled atypical CPP. Choroid plexus carcinomas usually classify as WHO 18 grade III. 19 CPP can show both an aneuploid or, like in our case, a normal karyotype (29). 20Malignant transformation of CPPs is a rare (30

  23

  scans. A prenatal detection may lead to a proper 1 counselling of the parents and perinatal management improving the short-and 2 intermediate-term outcome of children with CPP or similar benign intracranial 3 MI, Weil-Lara B, Herrero-Hernández A: Papilloma and carcinoma 6 of the choroid plexus in pediatric patients [in spanish]. Radiologia 49: 279Sainte-Rose C, Lellouch-Tubiana A et al.: Papillomas and carcinomas 9 of the choroid plexus in children. J Neurosurg 88: 521-8, 1998 10 5 Chow E, Reardon DA, Shah AB et al.: Pediatric choroid plexus neoplasms. Int J 11 Radiat Oncol Biol Phys 44: 249-54, 1999 12 6 Adra A, Mejides AA, Salman FA et al.: Prenatal sonographic 13 diagnosis of a third ventricle choroid plexus papilloma. Prenatal Diagnosis, Shiokawa Y, Kobayashi K et al.: Choroid plexus papilloma of the 16 third ventricle in the fetus. Case illustration. J Neurosurg 100: 224Onuma T, Kameyama M et al.: Hydrocephalus due to cerebrospinal 1 fluid overproduction by bilateral choroid plexus papillomas. Childs Nerv Syst 20Choroid plexus papilloma and carcinoma (Chapter 26). In Raghavan 6 D, Brecher ML, Johnson DH et al.: Textbook of Uncommon Cancer, 2nd edition, 7 John Wiley & Sons, Chichester: 335-40, 1999 8 14 Kamaly-Asl ID, Shams N, Taylor MD: Genetics of choroid plexus tumors. 9 Neurosurg Focus 20: E10, 2006 10 15 Rutherford J, Chu CE, Duddy PM et al.: Investigations on a clinically and 11 functionally unusual and novel germline p53 mutation. Br J Cancer 86: 1592., Salhia B, Weitzman S et al.: Evaluation of proliferative index and 14 cell cycle protein expression in choroid plexus tumors in children. Acta 15 Neuropathol 103: 1-10, 2002 16 17 Mueller W, Eum JH, Lass U et al.: No evidence of hSNF5/INI1 point mutations in 17 choroid plexus papilloma. Neuropathol Appl Neurobiol 30: 304-7Seal S, Hattingh L et al.: The neonatal form of Aicardi-Goutiéres 22 syndrome masquerading as congenital infection. Early Hum Dev 84: 783-5, 2008 23 I, Roche C, Martinez-Bermejo A et al.: Hypomelanosis of 1 ITO. A study of 76 infantile cases. Brain Dev 20: 36-43,1998 2 22 Sybert VP, Pagon RA: Hypomelanosis of Ito in a girl with plexus papilloma and 3 translocation (X;17). Hum Genet 93: 227, 1994 4 23 Bergsagel DJ, Finegold MJ, Butel JS et al.: DNA sequences similar to those of 5 simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl 6 J Med 326: 988-93, 1992 7 24 Small JA, Blair DG, Showalter SD et al.: Analysis of a transgenic mouse 8 containing simian virus 40 and v-myc sequences. Mol Cell Biol 5: 642-8, 1985 9 25 Blamires TL, Friedmann I, Moffat DA: Von Hippel-Lindau disease associated 10 with an invasive choroid plexus tumour presenting as a middle ear mass. J 11 Laryngol Otol 106: 429-35, 1992 12 26 Blamires TL, Maher ER: Choroid plexus papilloma. A new presentation of von 13 Hippel-Lindau (VHL) disease. Eye 6: 90-2, 1992 14 27 Patanakar T, Prasad S, Mukherji SK et al.: Cystic variant of choroid plexus 15 papilloma. Clin Imaging 24: 130-1, 2000 16 28 Murata M, Morokuma S, Tsukimori K et al.: Rapid growing cystic variant of 17 choroid plexus papilloma in a fetal cerebral hemisphere. Valera ET, Neder L et al.: Polyploidy in atypical grade II choroid 20 plexus papilloma of the posterior fossa. Neuropathology, 29: 293-8, 2009 21 30 Coates TL, Hinshaw DB Jr, Peckman N et al.: Pediatric choroid plexus 22 neoplasms: MR, CT, and pathologic correlation. Radiology 173: 81-8, 1989 23 Harding BN, Phipps KP et al.: Managment of choroid plexus 1 tumors in children: 20 years experience at a single neurosurgical centre. Polat P, Tüzün Y et al.: Ultrasound and Magnetic Resonance Imaging 4 Findings of Choroid plexus papilloma. Tr J Medical Sciences 29: 341-3, 1999 5 33 Otten ML, Riina HA, Gobin YP et al.: Preoperative embolization in the treatment 6 of choroid plexus papilloma in an infant. Case report. J Neurosurg 104: 429Niranjan A, Kondziolka D et al.: Gamma knife radiosurgery for 9 treatment resistant choroid plexus papillomas. J Neurooncol 90: 105-10, 2008 10 35 Jeibmann A, Wrede B, Peters O, Wolff JE, Paulus W, Hasselblatt M: Malignant 11 progression in choroid plexus papillomas. J Neurosurg 107: 199-202

Fig. 1 :Fig. 1 :Fig. 2 (Fig. 3 (Fig. 4 (Fig. 5 (Fig. 6 (

 1123456 Fig. 1: Illustration of choroid plexus papilloma within the posterior horn of the right lateral ventricle combined with ipsilateral ventriculomegaly Fig. 2 (30+3 gw): Trans-abdominal ultrasound-scan, transverse view, showing an echogenic tumor in the right lateral ventricle (arrows)

discussed case we saw a higher mitotic activity, leading to a classification 16 analogous to WHO grade II. Due to the higher grading in our case the tumor has to 17

		Choroid plexus papilloma -perinatal management
		page 9
	6	.
	7
	8 9	CPP-cells are similar to choroid-plexus-cells which are cuboidal epithelial cells based on papillary fibrovascular tissue. This explains why CPP-cells are able to F o r
	10	produce CSF (11). CPP normally consists of highly differentiated cells without P
	11 12 13 14 15 18	signs of increased mitotic activity, nuclear atypia, necrotic areas and/or altered vascularisation. Tumors consisting of these cells are classified as CPP WHO grade e e r I. Minor calcification of the fibrocascular stroma is not an uncommon sign. Expansion of cysts accompanying a CPP may be seen (27), deterioration of cerebral tissue through cystic development is found sporadically (28). In our be labelled atypical CPP. Choroid plexus carcinomas usually classify as WHO R e v i e w
	19	grade III.
	20	CPP can show both an aneuploid or, like in our case, a normal karyotype (29).
	21	Malignant transformation of CPPs is a rare (30).
	22

Table 1 :

 1 Diagnosis and outcome of CPP in former investigations

	Page 33 of 44				Journal of Clinical Ultrasound
	Study	Sex	No.	Localisation	Sonographic presentation:	time of diagnosis	Intervention	Outcome
			of cases		Adra´s Triad (6)
	Adra et al., 1994 female	1	third	Confiremd triad	33rd week of	no intervention	SPP and
				ventricle		gestation		neonatal death
	Buckle & Smith,	male	1	third	not sufficiently specified:	2 months	not	not specified
	2007			ventricle	Confirmed ventriculomegaly and		specified
					intraventricular tumor
	Frye et al., 2007 female	1	rigth lateral	no ventriculomegaly	2 months;	craniotomy and	clinical status
				ventricle		additionally	GTR at the age	(e.g. sleep
						revealing Aicardi-	of 7 years due to	disturbances)
						Syndrome	symptomatic	unchanged
							issues
	Fujimura et al.,	male	1	right and left	Confirmed triad	10 months	repeated left and	significant
	2004			lateral			right craniotomy	reduction of
				ventricle			with STR	excessive CSF-
								production
	Noguchi et al.,	not	1	third	not sufficiently specified:	40th week of	frontal	7 days post
	2004	specified		ventricle	Confirmed ventriculomegaly and	gestation	craniotomy on	interventionem:
					intraventricular tumor		day 15 with	subdural
							GTR without	effusions on
							shunting	treated side
	Otten et al., 2006 male	1	right lateral	Confiremd triad	4 months	embolisation	good
				ventricle			and sequential	neurological
							parietal	outcome at 4-
							craniotomy with	month follow-up
							GTR
	Patanakar et al.,	male	1	right lateral	Confiremd triad	30 months	no intervention	exitus letalis
	2000			ventricle
	Stafrace &	not	1	right	not sufficiently specified:	1 months	embolisation	not specified
					John Wiley & Sons