Primary amoebic meningoencephalitis in North Queensland: the paediatric experience.

Primary amoebic meningoencephalitis (PAM) is a fulminant, diffuse haemorrhagic meningoencephalitis caused by Naegleria fowleri, with an almost invariably fatal outcome. In Australia and the developed world, PAM remains a rare disease, although it is very likely that large numbers of cases go undetected in developing countries. N. fowleri is a thermophilic, free-living amoeba with a worldwide distribution. It is acquired when contaminated fresh water is flushed into the nose and penetrates the central nervous system via the cribriform plate. Clinical features are similar to those of bacterial meningitis, but it does not respond to standard therapy and rapid progression to death occurs in most cases. Some survivors have been reported; these patients received early treatment with amphotericin B in combination with a variety of other medications. Our review describes the local and worldwide experience of this disease and its clinical features, and discusses the associated diagnostic challenges. We hope that by detailing the local response to a recent case, and the outcomes of our public health campaign, we can improve the knowledge of this rare disease for doctors working in rural and remote Australia.

Fibrinogen Early In Severe paediatric Trauma studY (FEISTY junior): protocol for a randomised controlled trial.

INTRODUCTION: Trauma causes 40% of child deaths in high-income countries, with haemorrhage being a leading contributor to death in this population. There is a growing recognition that fibrinogen and platelets play a major role in trauma-induced coagulopathy (TIC) but the exact physiological mechanisms are poorly understood. METHODS AND ANALYSIS: This is a prospective multicentre, open-label, randomised, two-arm parallel feasibility study conducted in the emergency departments, intensive care units and operating theatres of participating hospitals. Severely injured children, aged between 3 months and 18 years, presenting with traumatic haemorrhage requiring transfusion of blood products will be screened for inclusion.Sixty-eight patients will be recruited and will be allocated to fibrinogen replacement using fibrinogen concentrate (FC) or cryoprecipitate in a 1:1 ratio. Fibrinogen replacement will be administered to patients with a FIBTEM A5 of ≤10. All other aspects of the currently used rotational thromboelastometry-guided treatment algorithm and damage-control approach to trauma remain the same in both groups.The primary outcome is time to administration of fibrinogen replacement from time of identification of hypofibrinogenaemia. Clinical secondary outcomes and feasibility outcomes will also be analysed. ETHICS AND DISSEMINATION: This study has received ethical clearance from the Children's Health Queensland Human Research Ethics Committee (HREC/17/QRCH/78). Equipment and consumables for sample testing have been provided to the study by Haemoview Diagnostics, Werfen Australia and Haemonetics Australia. FC has been provided by CSL Behring, Australia. The funding bodies and industry partners have had no input into the design of the study, and will not be involved in the preparation or submission of the manuscript for publication.The use of viscoelastic haemostatic assays and early fibrinogen replacement has the potential to improve outcomes in paediatric trauma through earlier recognition of TIC. This in turn may reduce transfusion volumes and downstream complications and reduce the reliance on donor blood products such as cryoprecipitate.The use of FC has implications for regional and remote centres who would not routinely have access to cryoprecipitate but could store FC easily. Access to early fibrinogen replacement in these centres could make a significant impact and assist in closing the gap in trauma care available to residents of these communities.Outcomes of this study will be submitted for publication in peer-reviewed journals and submitted for presentation at national and international scientific fora. TRIAL REGISTRATION NUMBER: NCT03508141.

Case Report: Fatal Pediatric Melioidosis Despite Optimal Intensive Care.

With prompt administration of appropriate antimicrobial therapy and access to modern intensive care support, fatal pediatric melioidosis is very unusual. We describe cases of two children in whom the possibility of melioidosis was recognized relatively early, but who died of the disease, despite receiving optimal supportive care. We discuss the resulting implications for bacterial virulence factors in disease pathogenesis.

A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer.

PURPOSE: The purpose of this research was to determine the safety, immunogenicity, pharmacokinetics, biodistribution, and tumor uptake of repeat infusions of a complementarity-determining region grafted humanized antibody (sibrotuzumab) directed against human fibroblast activation protein (FAP). EXPERIMENTAL DESIGN: A Phase I open-label dose escalation study was conducted in patients with cancers epidemiologically known to be FAP positive. Patients were entered into one of four dosage tiers of 5, 10, 25, or 50 mg/m(2) sibrotuzumab, administered weekly for 12 weeks, with trace labeling with 8-10 mCi of (131)I in weeks 1, 5, and 9. RESULTS: A total of 26 patients were entered into the trial (15 males and 11 females; mean age, 59.9 years; age range, 41-81 years). Twenty patients had colorectal carcinoma, and 6 patients had non-small cell lung cancer. A total of 218 infusions of sibrotuzumab were administered during the first 12 weeks of the study, with 24 patients being evaluable. One patient received an additional 96 infusions on continued-use phase for a total of 108 infusions over a 2-year period, and 1 patient received an additional 6 infusions on continued use. There were no objective tumor responses. Only one episode of dose-limiting toxicity was observed. Therefore, a maximum tolerated dose was not reached. Treatment-related adverse events were observed in 6 patients during the infusional monitoring period. Four of the 6 patients, 3 of whom had associated positive serum human antihuman antibody, were removed from the study because of clinical immune responses. Gamma camera images of [(131)I]sibrotuzumab demonstrated no normal organ uptake of sibrotuzumab, with tumor uptake evident within 24-48 h after infusion. Analysis of pharmacokinetics demonstrated a similar mean terminal t(1/2) of 1.4-2.6 days at the 5, 10, and 25 mg/m(2) dose levels, and with a longer mean t(1/2) of 4.9 days at the 50 mg/m(2) dose level. CONCLUSION: Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.

Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma.

The treatment of malignant lymphoma has improved over the past 20 years, but the majority of patients are not cured. New modalities using targeted therapy based on new information in molecular biology and immunology hold promise for better outcomes with less toxicity. We review data on the use of radiolabeled monoclonal antibodies directed against the CD20 antigen on malignant B cells. We discuss the major radionuclides available, iodine 131 ((131)I), tositumomab, and yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA) and present data on new approaches in labeling antibodies that have facilitated their use. Clinical trial data with the yttrium-labeled antibodies are discussed. The use of dosimetry as a means for predicting toxicity is discussed, and the questions of long-term toxicity (late effects) are addressed. These targeted approaches to the treatment of malignancy, and lymphoma in particular, hold great promise.

Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma.

We report updated time-to-event variables of a phase III randomized study comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20+ non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V.) dose of 90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2 I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m2) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for 90Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with 90Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with 90Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of > 5 years have been observed. These results confirm that 90Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study.

PURPOSE: To investigate the safety, response rate, progression-free and overall survival of patients with liver metastases treated with (90)Y (glass) radioembolisation in a prospective, multicenter phase II study. METHODS: 151 patients with liver metastases (colorectal n=61, neuroendocrine n=43 and other tumour types n=47) refractory to standard of care therapies were enrolled in this prospective, multicenter, phase II study under an investigational device exemption. Clinical/laboratory/imaging follow-up were obtained at 30 days followed by 3-month intervals for 1 year and every 6 months thereafter. The primary end-point was progression-free survival (PFS); secondary end-points included safety, hepatic progression-free survival (HPFS), response rate and overall survival. RESULTS: Median age was 66 (range 25-88). Grade 3/4 adverse events included pain (12.8%), elevated alkaline phospatase (8.1%), hyperbilirubinemia (5.3%), lymphopaenia (4.1%), ascites (3.4%) and vomiting (3.4%). Treatment parameters including dose delivery were reproducible among centers. Disease control rates were 59%, 93% and 63% for colorectal, neuroendocrine and other primaries, respectively. Median PFS was 2.9 and 2.8 months for colorectal and other primaries, respectively. PFS was not achieved in the neuroendocrine group. Median survival from (90)Y treatment was 8.8 months for colorectal and 10.4 months for other primaries. Median survival for neuroendocrine patients has not been reached. CONCLUSION: Patients with liver metastases can be safely treated with (90)Y microspheres. This study is the first to demonstrate technical and dose reproducibility of (90)Y glass microspheres between centers in a prospective setting. Based on these promising data, three international, multicenter, randomised phase III studies in colorectal and hepatocellular carcinoma have been initiated.

Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study.

We previously demonstrated that yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) radioimmunotherapy (RIT) was safe and effective for relapsed or refractory CD20(+), B-cell, non-Hodgkin lymphoma (NHL). We now provide long-term follow-up data in responding patients based on International Workshop Response Criteria. Complete (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%, 22%, and 22%, respectively (overall response rate 73%, 51% in CR/CRu). Mean time to progression (TTP) and duration of response (DR) in responders were 12.6 months and 11.7 months, respectively. At the maximum tolerated dose (0.4 mCi/kg [14.8 MBq/kg]), TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 months, respectively. Nine patients (24% of responding patients) had a TTP of more than 3 years. Long-term responders (> 5 years) have been identified. Ibritumomab tiuxetan produces durable responses in patients with indolent and diffuse large B-cell lymphoma.

Yttrium 90 ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory low-grade non-Hodgkin's lymphoma.

The treatment of malignant lymphoma has improved over the past 20 years, but the majority of patients are not cured. New modalities using targeted therapy based on new information in molecular biology and immunology hold promise for better outcomes with less toxicity. We review data on the use of radiolabeled monoclonal antibodies directed against the CD20 antigen on malignant B cells. We discuss the major radionuclides available, iodine 131 (131I), tositumomab, and yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA) and present data on new approaches in labeling antibodies that have facilitated their use. Clinical trial data with the yttrium-labeled antibodies are discussed. The use of dosimetry as a means for predicting toxicity is discussed, and the questions of long-term toxicity (late effects) are addressed. These targeted approaches to the treatment of malignancy, and lymphoma in particular, hold great promise. Semin Oncol 29 (suppl 2):87-92. Copyright © 2002 by W.B. Saunders Company.