Optic Nerve Sheath Viscoelastic Properties: Re-Examination of Biomechanical Behavior and Clinical Implications.

BACKGROUND: Meta-analyses show a variable relationship between optic nerve sheath diameter (ONSD) and the presence of raised intracranial pressure (ICP). Because optic nerve sheath (ONS) tissue can be deformed, it is possible that ONSD reflects not only the current ICP but also prior deforming biomechanical exposures. In this post hoc analysis of two published data sets, we characterize ONS Young's modulus (E, mechanical stress per unit of strain) and calculate threshold pressure for plastic deformation. METHODS: The authors of two previously published articles contributed primary data for these unique post hoc analyses. Human cadaveric ex vivo measurements of ONSD (n = 10) and luminal distending pressure (range 5 to 65 mm Hg) were used to calculate E and the threshold pressure for plastic deformation. Clinical in vivo measurements of ONSD and ICP during endotracheal tube suction from patients with traumatic brain injury (n = 15) were used to validate the ex vivo cadaveric findings. RESULTS: Ex vivo ONS estimate of E was 140 ± 1.3 mm Hg (mean ± standard error), with evidence of plastic deformation occurring with distending pressure at 45 mm Hg. Similar E (71 ± 10 mm Hg) was estimated in vivo with an average ICP of 34 ± 2 mm Hg. CONCLUSIONS: Ex vivo, ONS plastic deformation occurs at levels of pressure commonly seen in patients with raised ICP, leading to distortion of the ICP-ONSD relationship. This evidence of plastic deformation may illustrate why meta-analyses fail to identify a single threshold in ONSD associated with the presence of raised ICP. Future studies characterizing time-dependent viscous characteristics of the ONS will help determine the time course of ONS tissue biomechanical behavior.

Impact on the hepatic flow velocity after pediatric combined liver-kidney transplantation compared to isolated pediatric liver transplantation-A matched-pair analysis.

BACKGROUND: Combined liver-kidney transplantation (CLKT) in children is still a rarely performed procedure. Our aim was to analyze the effect of the simultaneous transplantation of the kidney in pediatric CLKT on the liver graft flow velocity, and vascular complications compared to singular liver transplantation (LTX) in children. METHODS: All pediatric CLKT performed at our institution from 1998 to 2016 were matched with singular LTX and retrospectively analyzed. RESULTS: Overall 30 CLKT were performed in 28 children (median age 8 years, range 1-16) and matched with 30 children undergoing singular LTX (median age 7.9 years, range 1-16). No significant differences were found concerning the systolic peak flow velocity of the hepatic artery (HA) or the resistance index (RI). Vascular complications of the hepatic vessels occurred in 16.7% (CLKT) and 6.7% (LTX). The 1-/5- and 10-year patient survival was 93.3%/93.3% and 93.3% (CLKT) and 100%/100% and 92.9% (LTX). 1-/5-and 10-year liver graft survival was 76.7%/73.2% and 73.2% (CLKT) and 84.4%/75.9% and 69.6% (LTX). CONCLUSION: The simultaneous transplantation of the kidney in CLKT had no negative impact on hepatic flow velocity or vascular complications. Frequent Doppler ultrasound examinations, accurate volume management, and avoidance of abdominal pressure might be an explanation for the results and an excellent graft- and patient survival.

Persistence of post-operative color Doppler abnormalities is linked to reduced graft survival in pediatric patients after liver transplantation.

Color Doppler US is a readily available imaging modality for the evaluation of liver transplants. The aim of our study was to evaluate the temporal course of color Doppler US findings in children after LTX and to investigate the effect of resolving and persisting abnormalities during follow-up on long-term outcome. All children who underwent LTX during January 2000 until December 2003 (155 LTX in 137 patients, 75 male and 62 female; mean age at LTX 4.1 ± 4.8 years; range, 0.1-16.3 years) were retrospectively evaluated. Following a predefined ultrasound protocol with prospective documentation, intraoperative, post-operative, and follow-up examinations were evaluated for color Doppler abnormalities. The time of occurrence and temporal course of the findings were recorded. Graft survival rates and graft survival times were compared. Abnormal color Doppler US examinations were noted in 98 of 155 grafts during the entire observational period (63.2%). In 57 of 98 grafts (58.2%), abnormalities were limited to the perioperative period (<30 days after LTX). Survival of grafts with transient perioperative abnormalities was similar to transplantations with regular color Doppler US examinations (graft survival rates, 80.7% vs 84.2%, P = .622; mean graft survival time, 2596.92 vs 2511.40 days, P = .67). Grafts with persisting color Doppler US abnormalities in the follow-up period (>30 days after LTX; 37/98 LTX, 37.8%) showed reduced survival compared with regular courses (graft survival rate 62.2% vs 80.7%, P = .047), indicating underlying organ-specific alterations. Standardized longitudinal evaluation during the perioperative and the follow-up period can enhance the prognostic capabilities of color Doppler US in children following LTX.

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.

BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.

Transcapsular arterial neovascularization of liver transplants increases the risk of intraoperative bleeding during retransplantation.

Arterial neovascularization of liver grafts can be a source of significant blood loss during retransplantation. This study evaluated the effect of transcapsular arterial neovascularization on intraoperative blood loss during retransplantation and long-term follow-up. Eleven consecutive patients with transcapsular arterial neovascularization (seven male, four female; nine children, two adults; mean age 12.3 ± 16.3 years) and the same number of matched control patients were analysed. Blood loss was calculated based on transfusion requirements. The volume of transfused units of red blood cells per kilogram bodyweight until hepatectomy and during the entire procedure was significantly higher in patients with neovascularization than in control patients (0.32 ± 0.21 vs. 0.14 ± 0.11, and 0.94 ± 0.83 vs. 0.36 ± 0.38 respectively; P-values 0.027). Neovascularization was associated with extensive intra-abdominal adhesions and a longer operating time until hepatectomy (175.6 ± 52.1 min vs. 124.3 ± 34.9 min, P-value 0.015). Postoperative revisions were performed more frequently in patients with neovessels. Graft survival did not differ between groups. Assessment for transcapsular arterial neovascularization should be included in preoperative Doppler ultrasound protocols to identify patients at risk of a complicated intra- and postoperative course in case of retransplantation.

Combined liver-kidney transplantation for children with autosomal recessive polycystic kidney disease (ARPKD): indication and outcome.

In ARPKD, mutations in the PKHD1 gene lead to remodeling of the kidneys and liver. These may result in progressive liver fibrosis with portal hypertension requiring combined liver and kidney transplantation (CLKT). There is currently no consensus on the indication for CLKT and data on long-term outcomes are scarce. We analyzed in detail the pretransplant liver symptomatology, laboratory and ultrasound data, histological studies, and genotypes in eight patients undergoing CLKT. The median age was 10.1 years (range 1.7-16) and median follow-up was 4.6 years (range 1.1-8.9). All patients had clinical signs of portal hypertension and abnormal ultrasound findings. Congenital hepatic fibrosis was present in all pretransplant biopsies (6 out of 8 patients) and in all explanted livers. All patients survived; liver and kidney graft survival was 72% and 88%, respectively. Liver and kidney function were stable in all patients with a median eGFR of 70 ml/min/1.73 m² (range 45-108 ml/min/1.73 m²). Height-SDS improved significantly after 12, 24, and 36 months (P = 0.016, 0.022 and 0.018 respectively). The indication for CLKT remains challenging and controversial. A favorable outcome for patients with ARPKD can be achieved by using the degree of portal hypertension, longitudinal ultrasound examinations, and preoperative liver histology as parameters for CLKT.

Prognostic Factors in High-Grade Osteosarcoma of theExtremities or Trunk: An Analysis of 1,702 Patients Treatedon Neoadjuvant Cooperative Osteosarcoma Study GroupProtocols.

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival ≥ 40, 41.6%; < 40, 60.2%; P = .012), tumor site (axial, 29.2%; limb, 61.7%; P < .0001), and primary metastases (yes, 26.7%; no, 64.4%; P < .0001), and for extremity osteosarcomas, also size (≥ one third, 52.5%; < one third, 66.7%; P < .0001) and location within the limb (proximal, 49.3%; other, 63.9%; P < .0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P < .0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P < .0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.

Time course of optic nerve sheath dilation: In vitro response characteristics to controlled pressure elevations.

BACKGROUND: Optic nerve sheath (ONS) dilation indicates intracranial pressure elevation under clinical conditions but limited data exist with regard to the dynamics of sheath expansion. OBJECTIVE: To assess the time course of ONS widening and its stability under controlled pressure conditions in vitro. METHODS: Pre-defined pressure steps up to 65 mmHg were applied to the perineural space of ex-vivo human optic nerves (n = 16). Using ultrasound, the optic nerve sheath diameter (ONSD) was monitored over 500 s. Re-tests at low-pressure levels concluded each experimental series. RESULTS: In most cases, 50% of the total diameter-change were achieved within 50 s after pressure onset and 95% of the maximal diameter after 200 s. The diametric gains in each experiment were strongly correlated with the applied pressure levels (coefficient of variance 0,96) within preparations with variability of the transfer function across preparations. The time course of the dilation was found to follow an approximate natural logarithmic function (R2 = 0.93-0.99). The re-test condition revealed unchanged time course properties (5% significance level) despite starting regularly from a higher baseline-diameter after preceding exposures. CONCLUSIONS: ONS dilation commences rapidly after pressure exposure with a predictable time course over 3-4 min. Elasticity changes presumably affecting trabecular structures cause upward shifts of the optic nerve sheath pressure response. Clinically, ONSD shifts should be considered in serial measurements for increasing intracranial pressure monitoring, but relevant response delays are absent for lower or higher changes of intracranial pressure.

Transcapsular arterial neovascularization after liver transplantation in pediatric patients indicates transplant failure.

PURPOSE: To identify transcapsular arterial neovascularization with Doppler ultrasonography (US) in pediatric patients after liver transplantation and to assess the frequency of the finding, its underlying causes, and its relevance in terms of clinical outcome. MATERIALS AND METHODS: The study was approved by the local ethics committee, with waived informed consent. All pediatric patients who underwent liver transplantation between January 2000 and December 2003 were retrospectively evaluated. Patients were followed up until June 2008, by using a predefined US protocol with prospective documentation. Of 182 consecutive liver transplantations performed in 162 patients (mean age, 4.5 years; range, 0.1-18.4 years) in this period, 25 patients with a total of 27 liver transplantations underwent US examinations conducted by multiple investigators and were primarily excluded. Student t tests and χ(2) tests were performed where appropriate. The Tarone-Ware test was used to compare transplant survival times. RESULTS: Transcapsular arterial neovascularization was noticed in 13 of 137 patients (9.5%) and in 13 of 155 liver transplants (8.4%). The mean time until arterial neovessels appeared was 157 days after liver transplantation (median, 97 days; range, 19-477 days). Arterial neovascularization was associated with pronounced transplant malperfusion and inflammatory changes (P < .001). Patients with transcapsular arterial neovascularization had a significantly shorter mean transplant survival time (1426.4 days ± 244.5 [standard error], with 95% confidence interval: 947.23, 1905.23, vs 2526.4 days ± 92.1, with 95% confidence interval: 2345.84, 2706.97; P = .008) and a higher retransplantation rate (53.8% vs 19.7%, P = .009). CONCLUSION: Transcapsular arterial neovascularization, detected with color Doppler US, occurred in 9.5% (13 of 137) of pediatric patients and 8.4% (13 of 155) of liver transplants and was associated with underlying malperfusion and inflammation. The diagnosis of transcapsular arterial neovascularization was associated with reduced graft survival times and a high retransplantation rate. The negative prognostic value of the sign may assist in a strategy of organ allocation.

Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group.

BACKGROUND: Solitary skeletal osteosarcoma (OS) manifestations distant from the site of the primary tumor rarely arise as only sign of disease recurrence. METHODS: This report reviews 38 patients with high-grade central OS of the limbs or axial skeleton and initial complete surgical remission (CR) who developed first recurrences as solitary osseous lesions distant from the primary tumor. The Cooperative Osteosarcoma Study Group (COSS) database was used to evaluate patient-, tumor-, and treatment-related variables and outcomes. RESULTS: Thirty-eight patients (27 males and 11 females; 36 limb and 2 axial primaries) developed solitary osseous recurrences a median of 2.1 years (range: 0.5-14.3) from primary diagnosis. Relapses involved axial (24), extremity (10), or craniofacial bones (4). Treatment for recurrence included surgery (28), radiotherapy (10), and chemotherapy (27). After a median follow-up of 1.9 years (range: 0.1-21.2) from first recurrence for all 38 patients and 5.5 years (0.3-21.2) for 16 survivors (10 in continuous second CR), 2- and 5-year overall and event-free survival (EFS) probabilities were 55% and 34% and 34% and 27%, respectively. A long interval to recurrence (>1.5 years) predicted for better overall (P < 0.001) and EFS (P = 0.005). For 21 patients achieving a second CR, 2- and 5-year overall and EFS probabilities were 81% and 61% and 52% and 49%, respectively, while only 1/17 others survived beyond 5 years (P < 0.001). Survivors (14/16) had also received second-line chemotherapy. CONCLUSION: First solitary skeletal recurrences of OS should be treated with curative intent. Some presumed bone metastases may represent second primary OSs.

Liver transplantation in children using organs from young paediatric donors.

Nowadays, most paediatric liver transplant recipients receive a split or other technical variant graft from adult deceased or live donors, because of a lack of available age- and size matched paediatric donors. Few data are available, especially for liver grafts obtained from very young children (<6 years). We analysed all paediatric liver transplantations between 1989 and 2009. Recipients were divided into five groups (1-5) depending on donor age (<1, ≥1 to <6, ≥6 to <16, ≥16 to <45, ≥45 years). Overall, 413 paediatric liver transplantations from deceased donors were performed; 1- and 5-year graft survival rates were 75%, 80%, 78%, 81%, 74% and 75%, 64%, 70%, 67%, 46%, and 1- and 5-year patient survival rates were 88%, 91%, 90%, 89%, 78% and 88%, 84%, 84%, 83%, 63% for groups 1-5, respectively, without significant difference. Eight children received organs from donors younger than 1 year and 45 children received organs from donors between 1 and 6 years of age. Overall, vascular complications occurred in 13.2% of patients receiving organs from donors younger than 6 years. Analysis of our data revealed that the usage of liver grafts from donors younger than 6 years is a safe procedure. The outcome was comparable with grafts from older donors with excellent graft and patient survival, even for donors younger than 1 year.

Value of ultrasound-guided percutaneous liver biopsy in children following liver transplantation.

OBJECTIVES: Pediatric liver transplant recipients often need to undergo liver biopsies for the detection and specification of complications such as acute or chronic graft rejection, infection, or drug toxicity. Complications resulting from liver biopsy are rare. The aim of our single-center retrospective study was to report on liver biopsy-related complications and, moreover, to assess the significance of histological findings in correlation with the suspected diagnosis. PATIENTS AND METHODS: Overall, 120 liver biopsies from 67 children were performed and analyzed. All of the biopsies were performed with ultrasound guidance using midazolam and ketamine. RESULTS: The overall incidence of complications was 5.0%, but most of these complications were mild. In 2 cases, however, the complications were severe and required surgical intervention in addition to further medical treatment.In about 92% of the cases, liver histology confirmed the previously suspected diagnosis based on clinical and clinical laboratory indications. CONCLUSIONS: We concluded that postliver transplantation liver biopsy in children seldom provides unexpected results and, even using ultrasound guidance, has led, albeit rarely, to serious complications. We therefore now accept potential delay in treatment and reserve liver biopsy for patients who fail to respond to therapy based on clinical judgment.

Schimke immunoosseous dysplasia: defining skeletal features.

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Comparative study of portal vein embolization versus portal vein ligation for induction of hypertrophy of the future liver remnant using a mini-pig model.

SUMMARY BACKGROUND DATA: The extent of hepatectomies is limited by the functional reserve of the remnant liver. The introduction of preoperative portal vein occlusion techniques to induce a preoperative hyperplasia of the future liver remnant has reduced the risk of postoperative liver failure. However, it has remained a matter of debate whether partial portal vein embolization (PVE) or suture ligation of the portal branches during exploration is the preferred technique. We compared both techniques under standardized experimental conditions in a large animal model by means of effectiveness and pathophysiologic differences. METHODS: Thirteen mini-pigs underwent portal vein ligation (PVL), 11 mini-pigs underwent PVE of 75% of the liver volume, and 6 underwent a sham operation. The animals were killed after 28 days. Laboratory liver function and damage parameters, lobar liver-to-body weight indices, portal and arterial flow alterations, and histologic changes were assessed. Ex situ arteriograms and portograms were performed to examine adaptive changes in the macroarchitecture of both vascular systems. RESULTS: The liver-to-body weight index of the nonoccluded lobe was highest after PVE (0.85) versus 0.6 (P < 0.05) after PVL. There was no significant reduction in global serum parameters reflecting total liver function. After 4 weeks, the PVL group consistently exhibited hepatopetal portal flow in the ligated lobes, which was present but significantly decreased after PVE. The ex situ angiography after PVE and PVL revealed the development of portal neocollaterals in the portal-occluded liver parts. CONCLUSIONS: Both PVL and PVE are able to induce hypertrophy of the future liver remnant. In comparison, PVE is the more effective technique to increase the future liver remnant. This is due to a more effective, durable occlusion of the portal branches. Formation of collaterals between occluded and nonoccluded liver parts seems to be the cause of inferior regeneration in the ligation group.

Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS: Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS: After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION: Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Diaphragmatic hernia resulting in enterothorax following pediatric liver transplantation: a rare complication.

Diaphragmatic hernia is a rare complication following solid organ transplantation. We here report three pediatric patients suffering from posttransplant enterothorax. One patient with biliary atresia presented with clinical signs of peritonitis without showing pulmonary symptoms four weeks following liver transplantation. The second patient was admitted with suspected pneumonia, whereas the third patient presented with recurrent abdominal pain over weeks and physical examination revealed the unexpected diagnosis of enterothorax. All patients received split liver transplants. Unspecific clinical signs mislead to suspected infectious complication under immunosuppression. No apparent risk factors for diaphragmatic hernia could be identified. Diaphragmatic hernia can present with a variety of atypical clinical symptoms. Severe or prolonged abdominal complains should lead to x-ray examination. We speculate that the split liver technique used in our center could lead to this rare complication due to the different anatomic position of the liver transplant in the abdomen.

Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.

PURPOSE: To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease. PATIENTS AND METHODS: A total of 1,702 consecutive newly diagnosed patients with high-grade osteosarcoma of the trunk or limbs registered into the neoadjuvant studies of the Cooperative Osteosarcoma Study Group before July 1998 were entered into an analysis of demographic, tumor-related, and treatment-related variables, response, and survival. The intended therapeutic strategy included preoperative and postoperative chemotherapy with multiple agents as well as surgery of all operable lesions. RESULTS: Axial tumor site, male sex, and a long history of symptoms were associated with poor response to chemotherapy in univariate and multivariate analysis. Actuarial 10-year overall and event-free survival rates were 59.8% and 48.9%. Among the variables assessable at diagnosis, patient age (actuarial 10-year survival > or = 40, 41.6%; < 40, 60.2%; P =.012), tumor site (axial, 29.2%; limb, 61.7%; P <.0001), and primary metastases (yes, 26.7%; no, 64.4%; P <.0001), and for extremity osteosarcomas, also size (> or = one third, 52.5%; < one third, 66.7%; P <.0001) and location within the limb (proximal, 49.3%; other, 63.9%; P <.0001), had significant influence on outcome. Two additional important prognostic factors were treatment related: response to chemotherapy (poor, 47.2%; good, 73.4%; P <.0001) and the extent of surgery (incomplete, 14.6%; macroscopically complete, 64.8%; P <.0001). All factors except age maintained their significance in multivariate testing, with surgical remission and histologic response emerging as the key prognostic factors. CONCLUSION: Tumor site and size, primary metastases, response to chemotherapy, and surgical remission are of independent prognostic value in osteosarcoma.

Pediatric transplantation: the Hamburg experience.

BACKGROUND: Since starting our program in 1989, 455 pediatric orthotopic liver transplantations have been performed using all techniques. In April 2001, we experienced our last in-hospital death of a pediatric liver-transplant recipient. Since then, all our liver-transplant children (n=170) were able to be discharged from the hospital. The aim of this study is to analyze the actual status of pediatric liver transplantation at the University of Hamburg and to find future perspectives to improve the results after pediatric liver transplantation. METHODS: From May 4, 2001 until September 8, 2004, 22 (13%) whole organs, 18 (11%) reduced-size organs, 79 (47%) split organs, and 51 (30%) organs from living donors were transplanted into 142 patients. One hundred forty-one were primary liver transplants, 25 retransplants, 3 third, and 1 fourth liver transplants. Of the 170 orthotopic liver transplantations (OLT), 31 (18%) were highly urgent (United Network of Organ Sharing [UNOS] I). RESULTS: After 170 consecutive pediatric liver transplants, no patients died during the hospital course (100% patient survival<3 months), but overall, 5 (2.9%) recipients died during further follow-up. The 3-month and actual graft survival rates are 93% and 85%, respectively. Twenty (11.8%) children had to undergo retransplantation. However, patient survival was not sustained by longer graft survival. Analyzing our series, we see that graft survival after reduced-size liver transplantation showed a significantly lower rate versus living-donor liver transplantation. CONCLUSION: The learning curve in pediatric liver transplantation has reached a turning point where immediate patient survival is considered the rule. The challenge is to increase graft survival to the same level. The long-term management of the transplant patients, with the aim of avoiding late graft loss and achieving excellent quality of life, will become the center of the debate.

Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.

PURPOSE: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. PATIENTS AND METHODS: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 µg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). RESULTS: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. CONCLUSION: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.