Home haemodialysis in Ireland.

BACKGROUND: Home haemodialysis (HHD) has the potential to impact positively on patient outcomes and health resource management. There has been rejuvenated international interest in HHD in recent years. AIM: We aimed to review the activity and outcomes of the Irish HHD Programme since inception (2009-16). DESIGN: Retrospective review. METHODS: Patient data were collected using the national electronic Renal Patient database (eMEDRenal version 3.2.1) and individual centre records. All data were recorded in a coded fashion on a Microsoft Excel Spread-sheet and analysed with Stata SE software. RESULTS: One hundred and one patients completed training and commenced HHD; a further fourty-five patients were assessed for HHD suitability but did not ultimately dialyse at home. Twenty patients switched to nocturnal HHD when this resource became available. The switch from conventional in-centre dialysis to HHD led to an increase in the mean weekly hours on haemodialysis (HD) and a reduction in medication burden for the majority of patients. The overall rate of arteriovenous fistula (AVF) as primary vascular access was 62%. Most HHD complications were related to access function or access-related infection. Over the 7-years, 29 HHD patients were transplanted and 9 patients died. No deaths resulted directly from a HHD complication or technical issue. CONCLUSIONS: Patient and technique survival rates compared favourably to published international reports. However, we identified several aspects that require attention. A small number of patients were receiving inadequate dialysis and require targeted education. Ongoing efforts to increase AVF and self-needling rates in HD units must continue. Psychosocial support is critical during the transition between dialysis modalities.

A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 ((131)I)-tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg (131)I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of (131)I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of (131)I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.

Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue.

PURPOSE: Radioimmunotherapy (RIT) is a promising treatment approach for B-cell lymphomas. This is our first opportunity to report long-term follow-up data and late toxicities in 29 patients treated with myeloablative doses of iodine-131-anti-CD20 antibody (anti-B1) and autologous stem-cell rescue. PATIENTS AND METHODS: Trace-labeled biodistribution studies first determined the ability to deliver higher absorbed radiation doses to tumor sites than to lung, liver, or kidney at varying amounts of anti-B1 protein (0.35, 1.7, or 7 mg/kg). Twenty-nine patients received therapeutic infusions of single-agent (131)I-anti-B1, given at the protein dose found optimal in the biodistribution study, labeled with amounts of (131)I (280 to 785 mCi [10.4 to 29.0 GBq]) calculated to deliver specific absorbed radiation doses to the normal organs, followed by autologous stem-cell support. RESULTS: Major responses occurred in 25 patients (86%), with 23 complete responses (CRs; 79%). The nonhematopoietic dose-limiting toxicity was reversible cardiopulmonary insufficiency, which occurred in two patients at RIT doses that delivered > or = 27 Gy to the lungs. With a median follow-up time of 42 months, the estimated overall and progression-free survival rates are 68% and 42%, respectively. Currently, 14 of 29 patients remain in unmaintained remissions that range from 27+ to 87+ months after RIT. Late toxicities have been uncommon except for elevated thyroid-stimulating hormone (TSH) levels found in approximately 60% of the subjects. Two patients developed second malignancies, but none have developed myelodysplasia (MDS). CONCLUSION: Myeloablative (131)I-anti-B1 RIT is relatively well tolerated when given with autologous stem-cell support and often results in prolonged remission durations with few late toxicities.

Importance of pre-treatment radiation absorbed dose estimation for radioimmunotherapy of non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma I-131 radioimmunotherapy data were analyzed to determine whether a predictive relationship exists between radiation absorbed doses calculated from biodistribution studies and doses derived from patient size. Radioactivity treatment administrations scaled to patient size (MBq/kg or MBq/m2) or fixed MBq doses do not produce consistent radiation absorbed dose to critical organs. Treatment trials that do not provide dose estimates for critical normal organs are less likely to succeed in identifying a clinical role for radioimmunotherapy.

Energy-based scatter corrections for scintillation camera images of iodine-131.

UNLABELLED: The use of high-dose 131I antibody therapy requires accurate measurement of normal tissue uptake to optimize the therapeutic dose. One of the factors limiting the accuracy of such measurements is scatter and collimator septal penetration. This study evaluated two classes of energy-based scatter corrections for quantitative 131I imaging: window-based and spectrum-fitting. METHODS: The window-based approaches estimate scatter from data in two or three energy windows placed on either side of the 364-keV photopeak using empirical weighting factors. A set of images from spheres in an elliptical phantom were used to evaluate each of the window-based corrections. The spectrum-fitting technique estimates detected scatter at each pixel by fitting the observed energy spectrum with a function that models the photopeak and scatter, and which incorporates the response function of the camera. This technique was evaluated using a set of Rollo phantom images. RESULTS: All of the window-based methods performed significantly better than a single photopeak window (338-389 keV), but the weighting factors were found to depend on the object being imaged. For images contaminated with scatter, the spectrum-fitting method significantly improved quantitation over photopeak windowing. Little difference, however, between any of the methods was observed for images containing small amounts of scatter. CONCLUSION: Most clinical 131I imaging protocols will benefit from qualitative and quantitative improvements provided by the spectrum-fitting scatter correction. The technique offers the practical advantage that it does not require phantom-based calibrations. Finally, our results suggest that septal penetration and scatter in the collimator and other detector-head components are important sources of error in quantitative 131I images.

Thrombocytopenia in dogs induced by granulocyte-macrophage colony-stimulating factor: increased destruction of circulating platelets.

Administration of recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) to normal dogs in previous studies induced an increase in peripheral blood neutrophils and a dose-dependent decrease in platelet counts. In six dogs that received the highest tested dose of rcGM-CSF (50 micrograms/kg/d) for a minimum of 12 days, the mean nadir of the platelet count was 46,000/microL (range, 4,000 to 91,000/microL) on day 9 +/- 1.1 after starting therapy, compared with a mean baseline platelet count of 398,000/microL (range, 240,000 to 555,000/microL). In three dogs, survival of autologous 111In-labeled platelets was reduced from a mean of 4.9 days to 1.3 days during the administration of rcGM-CSF. Biodistribution studies with gamma camera imaging indicated that there was an increase in mean hepatic uptake during the administration of rcGM-CSF, from 15% to 44% of the total injected 111In-labeled platelets at 2 hours, whereas splenic uptake was not significantly changed. In contrast, in two evaluable dogs who were recipients of 111In-labeled platelets from matched allogeneic donors receiving rcGM-CSF, platelet survival was not reduced and no increased hepatic uptake was noted. A third dog became alloimmunized to the matched donor platelets and was not evaluable. Immunohistologic studies of liver and spleen were performed with monoclonal antibodies specific for canine gpIIb/IIIa and P-selectin in dogs treated with rcGM-CSF and compared with untreated controls. On treatment, a marked reduction of platelets in the red pulp of the spleen was evident, and in general, the presence of platelet antigen in the liver was unchanged. Therefore, platelets were not being sequestered, but destroyed in the liver and spleen. The platelet antigens, P-selectin and gpIIb/IIIa, were identified in association with Kupffer cells in the liver, but no difference in the number of distribution of these Kupffer cells was found between controls and rcGM-CSF-treated dogs. In the spleen during rcGM-CSF treatment, most platelet antigens were associated with large mononuclear cells in the marginal zone. During administration of rcGM-CSF, CD1c and CD11c expression was increased on Kupffer cells. Platelet P-selectin expression and binding of leukocytes to circulating platelets were unchanged from baseline studies with rcGM-CSF treatment. In conclusion, during the administration of rcGM-CSF to dogs, a local process in the liver and spleen is induced resulting in thrombocytopenia.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation.

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen-specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.

Post therapy imaging in high dose I-131 radioimmunotherapy patients.

The biodistribution of a trace-labeled I-131 antibody is used to predict the biodistribution of a high dose I-131 antibody for therapy. Internal radiation dose estimates derived from the trace-labeled antibody have been used to determine the I-131 doses in a phase I escalating dose therapy trial for hematologic malignancy. To confirm the hypothesis that the distribution of a trace- and high-dose labeled antibodies are similar, both trace (7-11 mCi, 259-407 MBq) and high-dose (100-800 mCi, 3700-29600 MBq) I-131 radiolabeled antibody infusion were imaged in 12 patients who were treated for leukemia or lymphoma. With specialized imaging techniques using lead attenuation sheets, clearance data from organs were obtained from serial gamma camera images. Biological clearance half times of I-131 from both trace and therapy level doses were in agreement. An exception was a patient who developed human antimouse antibody before therapy, and subsequently had rapid clearance of the therapy dose. The method was feasible, yielded reproducible results, and provided critical data for relating therapy toxicity to radiation absorbed dose estimates.

A method for imaging therapeutic doses of iodine-131 with a clinical gamma camera.

Imaging therapeutic doses of 131I-labeled monoclonal antibody would provide valuable biodistribution data for dosimetry, but gamma cameras are unable to accurately handle the corresponding high counting rate. To image patients undergoing radioimmunotherapy, we attached 1.6- to 6.4-mm-thick Pb sheets to the front face of a high-energy parallel-hole collimator. With this method, we were able to acquire planar images of up to 700 mCi of radiolabeled antibody 1 hr after infusion. Monte Carlo simulations indicated that less than 7% of the events counted in the photopeak window were due to 364-keV photons that scattered in the Pb attenuator. Measurements indicated that the Pb sheets degraded system resolution by no more than 13%. A quantitative comparison of trace and therapy biodistribution data from planar images of the same patient was made using corrections for Pb sheet attenuation and camera deadtime.

Radiolabeled anti-CD45 monoclonal antibodies target lymphohematopoietic tissue in the macaque.

Despite bone marrow transplantation, many patients with advanced leukemia subsequently relapse. If an additional increment of radiation could be delivered to lymphohematopoietic tissues with relative specificity, the relapse rate may decrease without a marked increase in toxicity. We have examined the biodistribution of two 131I-labeled monoclonal antibodies reactive with the CD45 antigen in Macaca nemestrina. Three animals received 0.5 mg/kg BC8, an IgG1 of low avidity (6 x 10(7) L/mol). Three received 0.5 mg/kg AC8, an IgG2a of moderate avidity (5 x 10(8) L/mol), and two received 4.5 mg/kg AC8. Estimates of radiation absorbed dose demonstrated that these antibodies could deliver up to five times more radiation to lymph nodes, and up to 2.6 times more to bone marrow, than to lung or liver. The higher avidity AC8 antibody at 0.5 mg/kg was cleared more rapidly from blood and resulted in lower antibody uptake in lymph nodes than did BC8 at 0.5 mg/kg. Increasing the dose of AC8 to 4.5 mg/kg resulted in slower blood clearance and higher lymph node uptake. These studies suggest that radiolabeled anti-CD45 antibodies can deliver radiation with relative specificity to lymphohematopoietic tissues. This approach, in combination with marrow transplantation, may improve treatment of hematologic malignancies.

Considerations for imaging Re-188 and Re-186 isotopes.

Re-186 and Re-188 have been suggested for radioimmunotherapy because of their energetic beta particles, imageable gamma photons, and chemical properties similar to technetium. Because of this potential, these isotopes were evaluated before in vivo imaging was attempted. It was found that low-abundance, high-energy gamma photons present in these rhenium isotopes require a medium-energy collimator to yield optimal image resolution and count rate, which are critical factors in the performance of preliminary imaging studies on patients for antibody imaging and therapy.

Imaging and treatment of B-cell lymphoma.

Ten patients with non-Hodgkin's lymphoma have been evaluated as candidates for experimental radioimmunotherapy and five of those patients have been treated with a single high dose of iodine-131-(131I) labeled anti-pan B-cell antibodies. The evaluation protocol involved collecting biodistribution data by quantitation of gamma camera images and by tumor biopsy from trace labeled doses of antibody, to estimate the relative radiation dose delivered to normal organs and tumor sites. Each patient received up to three escalating mass doses (0.5 mg/kg, 2.5 mg/kg, and 10.0 mg/kg) of radioiodinated antibody for determination of the antibody amount that yielded the most favorable biodistribution for treatment. The millicuries of 131I-labeled to the optimal antibody dose for therapy was selected to deliver 1,000 rads (three patients) or 1,500 rads (two patients) to normal uninvolved organs. Because severe bone marrow toxicity was expected, all patients had their bone marrow cryopreserved prior to entry into the study. This report details the methods and results of quantitative imaging, biodistribution data collection, and absorbed radiation dose estimation in patients with lymphoma receiving high level radioimmunotherapy with 131I-labeled antibodies.

Effects of propylthiouracil on the biodistribution of an iodine-131-labeled anti-myeloid antibody in normal dogs: dosimetry and clinical implications.

Despite the use of near maximal doses of chemoradiotherapy, tumor recurrence remains the most frequent cause of treatment failure following marrow transplantation for leukemia. We have previously demonstrated that it is possible to selectively deliver radiation to the marrow space. In that study an initial short half-life of the radionuclide was observed. In this study we attempted to prolong the retention of the radioiodine in marrow through the use of propylthiouracil (PTU). When administered to normal dogs, PTU pretreatment resulted in improved marrow localization of 131I-labeled DM-5. There was no appreciable loss of activity from the marrow during the 2-4 hr postinjection time interval; a finding in contrast to the control animals where marrow activity declined a mean 45 +/- 0.5% over the same time period. Additionally, in contrast to controls, a rise in plasma trichloroacetic acid (TCA) nonprecipitable activity was not demonstrated in the PTU treated group during this 2-4 hr period. These results suggest that PTU's inhibition of deiodinases resulted in longer residence time of the radionuclide in its target tissue without adversely affecting distribution to non-target organs.

Specific marrow localization of an 131I-labeled anti-myeloid antibody in normal dogs: effects of a "cold" antibody pretreatment dose on marrow localization.

Tumor recurrence and regimen-related toxicity remain major obstacles in the successful use of marrow transplantation as therapy for hematologic malignancies. By attaching radionuclides to monoclonal antibodies (MoAbs) targeted at myeloid-associated antigenic determinants, a more effective and directed delivery of therapy may be possible without increasing toxicity. We investigated the biodistribution over time of an anti-myeloid antibody (DM-5) labeled with trace amounts of 131I in normal dogs. This study demonstrates the ability to target marrow with a high degree of selectivity, achieving marrow/blood ratios of 25-30:1 with the greatest concentration in any other organ being a tissue/blood ratio of 1.4:1 for stomach at 48 h. A pretreatment dose of unlabeled antibody effectively reduced early hepatic uptake by 80%, resulting in improved marrow localization with an estimated 58.6% of the injected dose localized in marrow within 2 h following infusion, compared to 32.8% without pretreatment. The marrow concentration clearance curve for the radioimmunoconjugate revealed an initial short half-life (4.75 h), suggesting rapid internalization, digestion, and release of free iodine (dehalogenation). This view was supported by a corresponding rise in trichloroacetic acid-non-precipitable activity during this period. Methods aimed at decreasing dehalogenation may result in longer residence time of the radionuclide within the marrow space, resulting in more effective tumor cell kill. This approach may provide a way to improve upon the current results obtained with marrow transplantation as treatment for patients with leukemia and other hematologic malignancies.

Preliminary validation of the opposing view method for quantitative gamma camera imaging.

We perform gamma camera imaging to generate data for estimation of internal radiation dose in our radioimmunotherapy candidates. Because of the inability of single photon emission computed tomography (SPECT) to account for patient attenuation variability without serious error, quantitative planar imaging was performed to estimate the radioactive content of normal organs. We undertook the following studies to further validate this method. A realistic fillable human phantom was used to determine the accuracy of I-131 filled organ estimation. A transmission scan of the unfilled phantom was produced with an I-131 filled flat flood source. Anterior and posterior planar images of the filled organs were acquired with region of interest determination of the activity in the organ. Correction by the attenuation factor and a camera calibration factor yielded the MBq in the organ. The procedure was also performed in a simple phantom. Three dogs were imaged and sacrificed to validate the technique in vivo. A high degree of accuracy in estimation of organ radioactive content was found to be present using the phantom and dog models. Use of this method requires further validation but provides a solid basis for estimation of internal radiation dosimetry in radioimmunotherapy planning.