Significant Renal Toxicity Research Articles

Clinical Study on Lobaplatin Combined with 5-Fu and Concurrent Radiotherapy in Treating Patients with Inoperable Esophageal Cancer

To investigate short- and long-term treatment effects and side reactions of lobaplatin plus 5-Fu combined and concurrent radiotherapy in treating patients with inoperable middle-advanced stage esophageal cancer. Sixty patients with middle-advanced stage esophageal squamous cell cancer were retrospectively analyzed. All patients were administered lobaplatin (50 mg intravenously) for 2 h on day 1, and 5-Fu (500 mg/m2) injected intravenously from day 1 to 5 for 1 cycle, in an interval of 21 days for totally 4 cycles. At the same time, late-course accelerated hyperfractionated three-dimensional conformal radiotherapy was performed. Patients were firstly treated with conventional fractionated irradiation (1.8 Gy/d, 5 times/week, a total of 23 treatments, and DT41.4 Gy), and then treated with accelerated hyperfractionated irradiation (1.5 Gy, 2 times/d, a total of 27 Gy in 9 days, an entire course of 6-7 weeks, and DT 68.4 Gy). All patients completed treatment, including 10 complete response (CR), 41 partial response (PR), 7 stable disease (SD), and 2 progressive disease (PD). The total effective rate was 85.0% (51/60). Thirty-nine patients had an increased KPS score. One-, 2-, and 3-year survival rates were 85.3%, 57.5%, and 41.7%, respectively. The median survival time was 27 months. The adverse reactions included myelosuppression, which was mainly degreeI and II. The occurrence rate of radiation esophagitis was 17.5%. No significant hepatic or renal toxicity was observed. Lobaplatin plus 5-Fu combined with concurrent radiotherapy is safe and effective in treating patients with middle-advanced stage esophageal cancer. However, this result warrants further evaluation by randomized clinical studies.

Coumarin derivatives from Ainsliaea fragrans and their anticoagulant activity.

Coumarin derivatives are an important class of C6–C3 plant metabolites that show a variety of bioactivities. Currently, most clinical anticoagulant agents are coumarins, such as warfarin, dicoumarol and acenocoumarol, and patients taking these drugs must be monitored for adverse reactions. In a search for safe and effective anticoagulant compounds from Chinese herbal medicine, a screening procedure on the whole plant of Ainsliaea fragrans was performed. The phytochemical investigation of this plant afforded five new coumarin derivatives, including a pair of natural 4-hydroxycoumarin enantiomers (1), a pair of coumarin enantiomers with a rare polycyclic pyrano[3-2c] carbon skeleton (2) and a 7-hydroxycoumarin derivative (3), together with 5 known biogenetically related compounds (4–8). Enantioseparation of 1 and 2 produced optically pure compounds 1a, 1b, 2a and 2b. The absolute configurations of the new compounds were confirmed by single-crystal X-ray diffraction analysis. In addition, we evaluated the anticoagulant activity of all isolates via activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) assays in vitro and in vivo. Of note, compound 3 displayed potent anticoagulant activity and no significant hepatic or renal toxicity, which could make it a promising agent for further preclinical evaluation for preventing abnormal blood clotting.

Phase II Trial of Dolastatin-10, a Novel Anti-Tubulin Agent, in Metastatic Soft Tissue Sarcomas.

Soft tissue sarcomas are uncommon malignancies with few therapeutic options for recurrent or metastatic disease. Dolastatin-10 (Dol-10) is a pentapeptide anti-microtubule agent that binds to tubulin sites distinct from vinca alkaloids. Based on the novel mechanism of action, limited activity of other anti-microtubular agents, and anti-neoplastic activity in pre-clinical screening of Dol-10, this multi-institutional phase II study was conducted to determine the objective response rate of Dol-10 in recurrent or metastatic soft tissue sarcomas that had not been treated with chemotherapy outside of the adjuvant setting. Dol-10 was given intravenously at a dose of 400 mug/m(2) and repeated every 21 days. Toxicities were assessed using the Common Toxicity Criteria (version 2.0). Radiographic studies and tumor measurements were repeated every two cycles to assess response [Miller AB, et al. Cancer 1981; 47(1): 207]. Dol-10 was associated with hematological toxicity and with some vascular toxicities. There was no significant gastrointestinal, hepatic or renal toxicity. There was one death on study due to respiratory failure. There were no objective responses in 12 patients treated with Dol-10. Based on this phase II trial, further study of Dol-10 on this schedule is not recommended in advanced or metastatic soft tissue sarcomas.

Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model

Abstractα-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, 211At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to 211At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of 211At-labeled anti-CD20 mAb ([211At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with 211At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [211At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.

Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice

Context. Methoxetamine is a ketamine analogue that has recently emerged as a novel psychoactive substance. Chronic ketamine use is associated with significant bladder and renal toxicity. Methoxetamine has been marketed as “bladder friendly”, but there is no data to be able to substantiate this claim. Objective. To characterise the patterns of bladder and renal toxicity associated with 3 months of methoxetamine administration in an animal model. Materials and methods. Two-month-old Institute of Cancer Research mice were administered 30 mg/kg methoxetamine intraperitoneally (n = 5) or saline (n = 3 control) for 3 months. The animals were then sacrificed and histological examination, immuno-cytochemistry using polyclonal anti-CD4 antibodies and sirius-red staining for collagen were performed. Results. The kidneys of methoxetamine-treated animals showed inflammatory cell infiltration, tubular cell necrosis and glomerular damage (1.9 ± 0.3% shrunken glomeruli in control, 9.8 ± 0.8% in methoxetamine-treated mice (p < 0.0001); 2.9 ± 0.3% tubular cell degeneration in control, 20.4 ± 1.1% in methoxetamine-treated mice (p < 0.0001)). There was a greater density of mononuclear cells in the bladder lamina propria and submucosa in methoxetamine-treated mice (43.0 ± 2.1 per 250 × 250 μm) than controls (7.1 ± 1.2 per 250 × 250 μm), p < 0.001. CD4-positive staining was seen in the bladder submucosa and lamina propria of all methoxetamine-treated mice and muscle-layer of two methoxetamine-treated mice; these changes were not seen in the control mice. There was an increase in sirius-red collagen in the bladder sub-mucosa and muscle-layer in the methoxetamine-treated mice compared with control mice. Discussion. This study has shown that 3 months of daily 30 mg/kg intra-peritoneal methoxetamine results in significant bladder and renal toxicity in mice. Changes in the bladder included inflammatory changes with subsequent fibrosis and changes in the kidney were seen at both a tubular and glomerular level. These changes are similar to those seen in comparable animal models of chronic ketamine administration. Further work is required to determine the time course of the onset of these effects and whether the effects are reversible with methoxetamine cessation.

Continuous renal replacement therapy allows higher colistin dosing without increasing toxicity

Abstract Polymyxins are ‘‘old’’ antimicrobials which were abandoned for almost 30 years because of significant renal and neurological toxicity. However, the alarming rise of multi-resistant Gramnegative bacterial infections worldwide has revived interest in these ‘‘forgotten’’ agents. Colistin (polymyxin E) is one of the main antibiotics of this class. It is most often administered as the pro-drug colistimethate sodium. Doses for treatment of systemic infections in adults range between 3 and 9 million IU per day. Colistin is increasingly used for treatment of pneumonia and bacteremia in critically ill patients. During their ICU stay, many of these subjects will need continuous renal replacement therapy (CRRT) because of acute kidney injury or an unstable hemodynamic condition. Based on recent pharmacological data and own experience, we postulate that patients undergoing CRRT may receive substantially higher doses of colistin (i.e., a high loading dose, followed by a maintenance dose up to 4.5 million IU tid). Treatment can be continued for a prolonged time period without increasing toxicity. CRRT counteracts colistin accumulation because the drug is continuously filtered and also significantly adsorbed in the bulk of the dialysis membrane. Implementing such ‘‘CRRT rescue’’ therapy does require the strict use of highly adsorptive dialysis membranes in association with citrate anticoagulation to increase membrane performance.

Astatine-211 Conjugated To Anti-CD20 Monoclonal Antibody Eliminates B-Cell Lymphoma In a Mouse Model

Stem cell rescue after myeloablative doses of beta particle emitting radiolabeled monoclonal antibodies targeting CD20 antigen can lead to remissions in up to 95% of lymphoma patients who previously failed conventional combination chemotherapy. While encouraging, toxicities with beta particle radioimmunotherapy (RIT) are significant and ∼50% of patients ultimately relapse. Higher doses of absorbed radiation to tumors have correlated with a reduced risk of disease recurrence but dose limiting toxicities prevent escalation. A potential advantage of alpha particle emitting radionuclides is the release of large amounts of energy linearly over a few cell diameters (∼50-80 mm) resulting in irreparable double-strand DNA breaks that overwhelm cellular repair mechanisms. As a result, alpha particles confer a unique capacity to kill individual targeted cells while causing minimal radiation damage to surrounding tissues. To explore alpha-emitter conjugated anti-CD20 RIT, a closo-decaborate(2-) [B10] labeling reagent was developed as a radiolabeling platform capable of providing critical stability to alpha particle-labeled biomolecules. 211At was chosen as a therapeutic radionuclide based on its high linear energy transfer, biologically relevant t1/2 (∼7.2 hr) and absence of toxic daughter radionuclide decay byproducts. Cell binding assays using CD20-expressing Ramos tumor cells demonstrated that B10 conjugated to the anti-CD20 monoclonal antibody (mAb) 1F5 (B10-1F5) was specific and that astatination did not impair antibody binding (211At-B10-1F5 binding was equivalent to 125I-B10-1F5). Blood clearance was similar for 125I-1F5, 211At-B10-1F5 and 125I-B10-1F5 in athymic nude- Foxn1nu mice (23.87 ±5.13 % injected dose/gram [ID/g], 19.41 ±3.27 %ID/g and 19.80 ±1.44% ID/g respectively) at 17 hr post infusion. In tissue biodistribution studies using nude mice bearing Ramos flank tumor xenografts (10 x106 cells injected) radioactivity was measured in blood, tumor and nonspecific organs harvested 24 hours after injection (n=5/group). Animals received either 125I-1F5, 211At-B10-1F5 and 125I-B10-1F5 (co-injected) or isotype matched control mAb 211At- B10-HB8181 and125I-B10-HB8181(co-injected). Measured activity in tumors was three-fold higher for 125I-1F5, 125I-B10-1F5 and 211At-B10-1F5 (7.62 ± 2.09%ID/g, 7.53 ± 1.59%ID/g and 9.28 ± 1.85%ID/g respectively) than for 125I-B10-HB8181 and 211At-B10-HB8181 controls (2.87 ± 0.35%ID/g and 3.45 ± 0.58%ID/g respectively). In non-target organs no appreciable difference in measured activity was seen with either 211At- or 125I-labeled B10-1F5 and their respective controls. Subsequent therapy studies performed in nude mice bearing Ramos flank tumor xenografts demonstrated only a moderate survival advantage after 211At-B10-1F5 [data not shown]. This finding was consistent with the hypothesis that the alpha particle's short path length may not be ideally suited to models of “bulky” disease. In contrast, therapy studies using disseminated Ramos and Granta tumor cells introduced into NOD-SCID mice suggest a role for alpha particle based RIT in “non-bulky” disease models. In these studies NOD-SCID animals received 1x106 tumor cells iv 48 hours prior to 211At-B10-1F5 (10 μCi or 15 μCi) or control 211At-B10-HB8181 (n=10/group). Stem cell rescue was performed 48 hours after the RIT. Eighty days after treatment 80% of animals receiving 15 μCi of 211At-B10-1F5 and 70% of animals in the 10 μCi treatment group were alive and tumor free while no animals in the non-binding 211At-B10-HB8181 (10 μCi or 15 μCi) control groups survived beyond day 47 (Figure). Blood counts, serum creatinine and transaminase levels measured in 211At-B10-1F5 treated animals ∼180 days after RIT demonstrated no significant long-term bone marrow, renal or liver toxicity. 211At-B10-1F5 can eliminate CD20 expressing tumor cells in this mouse model and further study appears to be warranted. Disclosures: No relevant conflicts of interest to declare.

Targeted radiotherapy with tumor vascular homing trimeric GEBP11 peptide evaluated by multimodality imaging for gastric cancer

Targeted radiopharmaceutical is an effective treatment for solid tumors. By labeling with radionuclides, targeting peptide could achieve both noninvasive diagnosis and targeted radionuclide therapy. In order to evaluate the potential applicability of GEBP11 peptides in diagnosis and radiotherapy of gastric cancer, in this study, iodine 131 labeled GEBP11 peptides, including a novel bifid PEGlylated GEBP11 trimer and its corresponding monomer, were developed. The clinical potential of GEBP11 peptides, such as tumor binding affinity and antitumor efficacy was demonstrated and assessed with multimodality imaging methods. Cerenkov and SPECT imaging showed higher tumor uptake for 131I-2PEG-(GEBP11)3 (P<0.05, day 1; P<0.01, day 2; vs. monomer). Biodistribution studies indicated higher tumor accumulation and better T/NT of 131I-2PEG-(GEBP11)3. Bioluminescence imaging exhibited a significant tumor growth suppression in 131I-2PEG-(GEBP11)3 treated group (P<0.001 vs. control; P<0.01 vs. monomer). After treatment with 131I-2PEG-(GEBP11)3, the tumor volume and vasculature decreased significantly, and the survival time was prolonged to 75.5days. Meanwhile, no significant hepatic or renal toxicity was observed with 131I-2PEG-(GEBP11)3 administered. In conclusion, 131I-2PEG-(GEBP11)3 could be a promising candidate for peptide-based targeting therapy of gastric cancer. 2PEG-(GEBP11)3 might be a potential drug delivery vehicle for the antiangiogenic therapy of gastric cancer.

Selective cyclooxygenase-1 inhibition improves collateral vascular reactivity in biliary cirrhotic rats

BackgroundEvidence has demonstrated that overproduction of prostacyclin (PGI2) is critical in the pathogenesis of splanchnic hyposensitivity to vasoconstrictors in the cirrhotic state. The biosynthesis of PGI2 is through cyclooxygenase (COX). This study evaluated which isoform of COX is dominant in the mechanism of collateral vascular reactivity of biliary cirrhotic rats. MethodsThree groups of formalin-injected common bile duct-ligated (FBDL) induced cirrhotic rats received two doses of: (1) selective COX-1 inhibitor (SC-560 2 mg/kg); (2) COX-2 inhibitor (NS-398 2 mg/kg); (3) dimethyl sulfoxide (control). Subsequently, the rats were kept in metabolic cages for 24 hours to collect urine. Thereafter, the systemic and portal hemodynamics and renal function were measured. In another series, using in-situ collateral perfusion model, the collateral vascular responses to arginine vasopressin (AVP) were measured in the subject rats after preincubation of vehicle (Krebs solution), SC-560 (5 μM) or NS-398 (10 μM). ResultsThe mean arterial pressure, heart rate, and portal pressure were similar among SC-560-treated, NS-398-treated, and control groups. Additionally, there was no significant difference in the calculated creatinine clearance rates among these three groups. SC-560 preincubation significantly enhanced the pressor effect of AVP at the concentration of 3M × 10−9 M (11.0 ± 1.0 mmHg vs. 6.4 ± 0.6 mmHg, p = 0.002) in the cirrhotic rats. ConclusionThere was no significant hemodynamic change and renal toxicity after acute administration of COX inhibitor in the FBDL-induced cirrhotic rats. Preincubation of selective COX-1, but not COX-2, inhibitor could enhance collateral vascular response to AVP, indicating that COX-1 plays a major role in the collateral vascular reactivity.

Use of sodium bicarbonate to promote weight gain, maintain body temperature, normalize renal functions and minimize mortality in rodents receiving the chemotherapeutic agent cisplatin

A simple method to reduce adverse effects of the chemotherapeutic agent cisplatin on animal health is described. Animals receiving normal saline (0.9% NaCl) s.c. prior to once weekly injections of cisplatin (3mg/kg i.p.×3 or 4 weeks) exhibited failure of weight gain, lowered body temperature, elevations in creatinine and ketone levels and increased kidney weight ratios. By contrast, rats treated with sodium bicarbonate (4% NaHCO3 in saline s.c.) prior to cisplatin (3mg/kg i.p.×3 or 4 weeks) exhibited normal weight gain, body temperature, creatinine and ketone levels, as well as normal kidney weight ratios (over 16 or 28 days, respectively). Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in both groups. Our studies suggest that NaHCO3 pretreatment promotes animal health and minimizes weight loss, body temperature dysregulation and signs of renal toxicity (i.e. increases in creatinine and kidney weight ratio) following repeated cisplatin treatment without altering the development of chemotherapy-induced peripheral neuropathy.

Incidence and predisposing factors of vancomycin-induced nephrotoxicity in children.

IntroductionTo investigate the pattern of vancomycin-associated nephrotoxicity in children and to examine potential predisposing factors for nephrotoxicity, including average serum trough concentrations ≥10 μg/mL.MethodsPatients ≥1 week old to ≤15 years with normal baseline serum creatinine values who received vancomycin for ≥48 h between October 2010 and September 2012 were retrospectively evaluated. Nephrotoxicity was defined as a serum creatinine increase of ≥0.5 mg/dL or ≥50% baseline increase over 2 days. Patients with average serum trough concentrations ≥10 μg/mL were compared with a lower trough group.ResultsRenal toxicity occurred in 72 (27.2%) of the 265 studied pediatric cases. High trough vancomycin levels ≥10 μg/mL were presented in 59 pediatric patients suffering from nephrotoxicity. Using multiple regression analysis, cases admitted to the intensive care unit (ICU) and to whom aminoglycoside medication was administered concurrently with vancomycin medication showed a significant high renal toxicity incidence [odds ratio (OR) 2.91; 95% confidence interval (CI) 1.70, 8.61; P value <0.03)] and (OR 9.11; 95% CI 4.11, 24.13; P < 0.05), respectively.ConclusionRenal function tests and continuous monitoring of vancomycin trough levels for children receiving vancomycin therapy, especially admitted to the ICU and given other aminoglycoside medications, are essential.

Metabonomics: on the Road to Detect Diagnostic Biomarkers in Endemic (Balkan) Nephropathy. Evaluation in a Retrospective Pilot Project

Introduction: Endemic (Balkan) Nephropathy is a chronic renal disease mainly affecting rural populations in the valleys of the Danube. In the absence of renal replacement therapy, it leads to fatal kidney failure and is significantly associated with upper urothelial carcinoma. Bread poisoning with aristolochic acids is now widely accepted. The source of this toxic substance is considered to be Aristolochia clematitis, a perennial plant that invades farming fields. The poisoning with aristolochic acids was suggested when clinical and histopathological changes similar to those observed in the Balkan patients were reported in several cases of nephropathy in Belgian patients unintentionally exposed to aristolochic acids during a Chinese herbs diet. Those clinical and histopathological features were then reproduced in laboratory experimental models. Methods: Using metabonomics, an emerging dynamic technique that allows an effective mapping of alterations in endogenous metabolites levels in biofluids and tissues, we evaluated early signs of renal toxicity from extra urine samples collected in a rat model of intoxication with aristolochic acids. Results: Changes in urine composition were consistent with a proximal tubular damage, most likely initiated by a mitochondrial default and an inappropriate response to oxidative stress. The same metabonomic approach was applied to surplus of urine samples collected from Belgian and Croatian patients in clinical and epidemiological studies, respectively. It allowed a clear discrimination of the Belgian patients from a database of healthy volunteers. On the other hand, a trend to discrimination was noticed when comparing urine samples collected from individuals living in Croatian endemic regions as compared to Croatian non endemic villages. Finally, when included in the same analysis, both Belgian and Croatian patients displayed similar urine metabolic signatures, suggesting a common etiology of both diseases.

High-Dose, Extended-Interval Colistin Administration in Critically Ill Patients: Is This the Right Dosing Strategy? A Preliminary Study

Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached. All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded. Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment. Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity.

Low-Dose Clofarabine Has Significant Activity in High-Risk Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia Post-MDS (sAML) After Azacitidine (AZA) Failure: Interim Results of the GFM Clo08 Dose Escalating Phase I/II Study (NCT0106325)

Abstract 609▪▪This icon denotes a clinically relevant abstract Background:Clofarabine (CLO) alone has shown antileukemic activity in MDS and AML, including sAML, at doses ranging from 15 to 40 mg/m2, although with significant myelosuppression and toxicity. Patients with high-risk MDS or sAML who failed AZA have a median OS of only 5 months (Prébet, JCO, online), and no established drug therapy is available for such patients. In this Phase I/II dose escalating study (NCT0106325), we explored safety and activity of CLO at lower dosing levels (DLs), in such patients. Methods:A standard IV, D1-5 and an extended D1, 3, 5, 8 and 10, administration schedules were studied in parallel, using a standard 3+3 design. Three DLs (CLO 5, 7.5 and 10 mg/m2, daily) were planned. Dose limiting toxicities (DLTs) were defined as any grade >3 non-hematological toxicity, excluding bleeding, infections or febrile neutropenia, or as any delayed cytopenias past D56, defined here as blood counts less than 50% of baseline counts. Responses were evaluated according to IWG 2006 MDS criteria or AML IWG criteria after courses 1 and 2, administered within 56 days. Patients in CR/PR after course 1 could receive up to 7 maintenance courses with only 3 daily infusions at same dosing. Patients in CR/PR or with stable disease after course 2 could receive up to 6 maintenance courses. If DLTs after course 1 were observed in less than 1 of 3 or 2 of 6 patients, dose escalation was permitted. If 2 or more DLTs were observed after course 1, exploration of lower intermediate DLs was planned. Patients with de novo MDS or sAML who failed at least 6 courses of AZA were eligible, if not candidates to intensive chemotherapy. Exclusion criteria included renal dysfunction (MDRD<50 ml/mn), bilirubin>1.5 ULN, liver function tests >2.5 ULN, ECOG score >2, and uncontrolled infection. Patients:Between November 2009 and July 2011, 19 Patients (10F, 9M) were enrolled, at DL1 (5 mg/m2, N=9) and DL2 (7.5 mg/m2, N=10), Median age was 72 years (62-90), WHO diagnosis were: RAEB 1 (N=1), RAEB 2 (N=8), sAML (N=10), including 7 patients with <30% marrow blasts). Cytogenetics was normal in 4 (3 RAEB, 1 AML), complex or with abn chr. 7 in 11 (8 sAML, 3 RAEB), and inv3, +8, 5q and 11q, del9q in 4 patients. Median duration of MDS phase, before entry, was 20 months (9-161). Responses to prior treatment with AZA included 6 CR, 2 marrow CR (mCR) and 4 stable with HI-E, 6 failures and 1 stable w/o HI, after a median number of AZA cycles of 10 (6-34), 11 (6-26) and 6 (6-8) respectively. Eleven patients had only received AZA and eight AZA and 1 to 3 other treatment lines, excluding growth factors. Results:(Table 1) All patients were evaluable for DLTs and response after one cycle. In the D1-5 cohort: one DL1 patient was classified as failure and non-hematological DLT (due to likely unrelated sudden death on D55, before evaluation), and one DL2 patient with mCR as DLT, due to prolonged thrombocytopenia beyond D56. One sAML patient was classified as failure due to early death linked to sepsis, but not as DLT per protocol. In the D1-10 cohort, no DLT was observed after cycle 1. Fifteen patients were eligible for an identical second course, as 2 patients had early death and 2 CR/PR. Twelve patients received a second course, with only 1/8 evaluable for response after course 2, improving response. This patient with mCR obtained durable HI-E and P after course 2. No significant liver or renal toxicity was observed in both cohorts. Seven patients were hospitalized after first course for fever or bleeding (3/9 in DL1/5mg/m2 and 4/10 in DL2/7.5mg/m2 cohorts). Overall, 6 of the 19 patients (32%) had a response after a single course including 2CR/PR and 4 of the 6 responses were seen at the 7.5 mg/m2 dose level.Table 1D1-5 CohortD1-10 CohortAllDL1 (5mg/m2)Overall Response0/62/3 (1mCR, 1 HI-E and P2/9DLT1/601/9DL2 (7.5mg/m2)Overall Response2mCR/7, incl. 1 HI-E and P2/3 (1CR, 1PR)4/10DLT1/701/10All Dosing levelsOverall Response2/134/66/19DLT2/130/62/19 Conclusion:In this dose escalating study in MDS or sAML patients who had failed azacitidine, low-dose clofarabine had significant activity and was administered as an outpatient therapy in most, although hospitalization due to myelosuppression was frequent, even at this low dosing. The extended alternate day (D1-10) schedule may be better tolerated and at least as efficient as the standard D1-5 schedule, although a larger number of patients is required to conclude. Dose escalation in the trial is continuing. Disclosures:Off Label Use: low dose Clofarabine in MDS after AZA failure. Vey:GENZYME: Honoraria. Dombret:GENZYME: Honoraria. Fenaux:GENZYME: Honoraria. Gardin:GENZYME: Honoraria, Research Funding.

Association between remote organ injury and tissue polyamine homeostasis in acute experimental pancreatitis – treatment with a polyamine analogue bismethylspermine

Experimental pancreatitis is associated with activation of polyamine catabolism. The polyamine analog bismethylspermine (Me2Spm) can ameliorate pancreatic injury. We investigated the roles of polyamine catabolism in remote organs during pancreatitis and explored the mechanism of polyamine catabolism by administering Me2Spm. Acute pancreatitis was induced by an infusion of 2 or 6% taurodeoxycholate before Me2Spm administration. Blood, urine and tissues were sampled at 24 and 72h to assess multi-organ injury and polyamine catabolism. The effect of Me2Spm on mortality in experimental pancreatitis was tested separately. Liver putrescine levels were elevated following liver injury. Me2Spm increased the activity of spermidine/spermine N1-acetyltransferase (SSAT) and depleted the spermidine, spermine or putrescine levels. Lung putrescine levels increased, and SSAT and spermine decreased following lung injury. Me2Spm enhanced the activity of SSAT and decreased the spermidine and spermine levels. Renal injury was manifested as an increase in creatinine or a decrease in urine output. Decreases in kidney SSAT, spermidine or spermine and an increase in putrescine were found during pancreatitis. In the 2% taurodeoxycholate model, Me2Spm decreased urine output and raised plasma creatinine levels. Me2Spm increased SSAT and decreased polyamines. Excessive Me2Spm accumulated in the kidney, and greater amounts were found in the 6% taurodeoxycholate model in which this mortality was not reduced by Me2Spm. In the 2% taurodeoxycholate model, Me2Spm dose-dependently induced mortality at 72h.Like pancreatic injury, remote organ injury in pancreatitis is associated with increased putrescine levels. However, Me2Spm could not ameliorate multi-organ injury. Me2Spm administration was associated with significant renal toxicity and induced mortality, suggesting that the current dose is too high and needs to be modified.

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

This study tested the principle that (68)Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with (177)Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with (68)Ga-DOTATATE PET/CT. The criterion of eligibility for (177)Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Of the 8 children imaged, 6 had abnormally high uptake on the (68)Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of (177)Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. (68)Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with (177)Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with (177)Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial.

Incidence and Response to Treatment of Adenovirus (ADV) infection With cidofavir (C) in Pediatric Patients After Allogeneic HCT

ADV infection occurs frequently and has a high mortality after HCT. The antiviral cidofavir has activity against ADV, but has significant renal and marrow toxicity. We report our centers incidence of ADV and its association with type of transplant and GVHD (clinically significant requiring > 1mg/kg solumedrol for at least 2 weeks). Between August 2002 and June 2010 76 patients received allogeneic HCT's. ADV infection was documented in 19 (25%). The initial site of infection was GI in 18 and GU in 1.

4-Step Renal Dosimetry Dependent on Cortex Geometry Applied to 90Y Peptide Receptor Radiotherapy: Evaluation Using a Fillable Kidney Phantom Imaged by 90Y PET

Accurate dosimetry in (90)Y peptide receptor radionuclide therapy (PRRT) helps to optimize the injected activity, to prevent kidney or red marrow toxicity, while giving the highest absorbed dose to tumors. The aim of this study was to evaluate whether direct (90)Y bismuth germanate or lutetium yttrium orthosilicate time-of-flight PET was accurate enough to provide dosimetry estimates suitable to (90)Y PRRT. To overcome the statistical uncertainty arising from the low (90)Y positron counting rate, the computation of the cortex mean-absorbed dose was divided into 4 steps: delineation of the cortex volume of interest (VOI) on the CT scan, determination of the recovery coefficient from the cortex VOI using the point-spread function of the whole imaging process, determination of the mean cortex-absorbed dose per unit cumulated activity in the cortex (S(cortex←cortex) value) from the cortex VOI using a (90)Y voxel S value kernel, and determination of the number of decays in the cortex VOI from the PET reconstruction. Our 4-step method was evaluated using an anthropomorphic abdominal phantom containing a fillable kidney phantom based on the MIRD kidney model. Vertebrae with an attenuation similar to that of bone were also modeled. Two tumors were modeled by 7-mL hollow acrylic spheres and the spleen by a plastic bag. Activities corresponded to typical tissue uptake in a first (90)Y-DOTATOC cycle of 4.4 GBq, considered as free of significant renal toxicity. Eight successive 45-min scans were acquired on both systems. Both PET systems were successful in determining absorbed dose to modeled tumors but failed to provide accurate red marrow dosimetry. Renal cortex dosimetry was reproducible for both PET systems, with an accuracy of 3% for the bismuth germanate system but only 18% for the lutetium yttrium orthosilicate time-of-flight system, which was hindered by the natural radioactivity of the crystal, especially in the most attenuated area of the kidney. This study supports the use of direct (90)Y PET of the first PRRT cycle to assess the kidney-absorbed dose and optimize the injected activity of the following cycles.

Nephrotoxicity of Cancer Treatment in Children

Chronic renal impairment in children with cancer may be caused by the malignant process itself or result from adverse effects of treatment including cytotoxic drugs, radiotherapy, surgery or supportive treatment. Although severe renal chronic disease is uncommon, occurring in only 0.8% of long-term survivors of childhood cancer, 1.9% of all cases of established renal failure are due to malignancy and 0.8% to drug nephrotoxicity. The relative risk of severe renal chronic disease (compared with siblings) is 8.1, and that of renal failure or the need for dialysis is 8.9. The cytotoxic drugs most likely to cause important chronic nephrotoxicity are ifosfamide and cisplatin, both of which are used widely in many solid tumors and may cause chronic glomerular and/or renal tubular toxicity in 30–60% of treated children. Significant renal toxicity is less frequent with other chemotherapeutic drugs, but may result from treatment with carboplatin, methotrexate and nitrosoureas. Other cytotoxic drugs occasionally cause specific patterns of glomerular or tubular toxicity in children. Partial or unilateral nephrectomy leads to hypertrophy and hyperfiltration of the remaining renal tissue, and may result in microalbuminuria, hypertension and in rare cases, chronic renal impairment. Radiotherapy to a field including renal tissue may cause late onset chronic renal damage, manifest by hematuria, proteinuria, hypertension and anemia, sometimes progressing to chronic renal failure. Chronic nephrotoxicity is also common in survivors of hemopoietic stem cell transplantation, and is often multifactorial with contributions from prior chemotherapy, total body irradiation, immunosuppressive drugs and transplant complications, such as infection or hemorrhage. Patients at risk of renal damage should be monitored regularly with a defined surveillance protocol to enable timely management. General measures often employed to prevent or reduce nephrotoxicity include the use of intravenous hydration during drug administration and avoidance of known risk factors, such as high drug doses. Although numerous potentially nephroprotective drugs have been suggested and investigated, none have yet been introduced into clinical use in children due to the lack of proven efficacy. Improved understanding of the pathogenesis of nephrotoxicity is necessary to reduce the frequency and severity of this potentially serious complication of treatment in children with cancer.

Long-term survival and toxicity profile of patients with disseminated neuroendocrine tumors following multiple cycles of high activity 111In pentetreotide therapy.

e13545 Background: We have previously reported clinical response to multiple doses of high activity 111In pentetreotide in patients with disseminated neuroendocrine tumors. Here we report long term renal toxicity and survival following multiple 500 mCi doses of 111In-pentetreotide. Methods: In a nonrandomized trial, 83 patients (50 men, 33 women) with disseminated neuroendocrine tumor (stages III to IV) received 500mCi doses of In-111 pentetreotide therapy without co-administration of amino acid solution. Twenty-one patients received one therapy with an average dose of 489mCi/patient (390-513 mCi) and average renal dose of 330 rad (134-712 rad). Forty-one patients received two cycles of therapies with an average dose 977mCi/patient (893-1,012 mCi/patient) and cumulative renal dose of 566 rad (63-578 rad). Twenty-one patients received three therapies with an (average dose 1,464 mCi/patient (1,419-1,495mCi) and cumulative average renal dose of 665 rad (329-2,273 rad). Patients were evaluated for evidence of renal toxicity using NCI common toxicities criteria and followed for an average of 28.64 months (1.2-50.6 months). For patients with more than one therapy, data is reported after the last cycle of therapy. Kaplan Meyer survival analysis was conducted on 65 patients followed for 12 months or more. Results: Four patients had grade 1renal toxicity immediately following therapy. Of these patients 1 patient received 1 therapy, 1 patient received 2 therapies and 2 patients received 3 therapies. There were no reports of significant renal toxicity. No correlation to absorbed kidney dose was found. Average survival time was 23.4 months (1.2-50.6 months). Conclusions: Multiple 500 mCi doses of 111In-pentetreotide therapy are effective in patients with progressive disseminated neuroendocrine tumors, with minor acute renal toxicity. No long-term toxicity was observed at doses up to 1,495 mCi/ patient. The toxicity profile of this regimen suggests the opportunity for further dose escalation. No significant financial relationships to disclose.