Background: Feline nasal lymphoma (NLSA) is a condition for which no standard of care exists. Hypothesis: There is no difference in survival times of cats with NLSA treated with single or multimodality therapy. Animals: Records from 97 cats diagnosed with NLSA were examined. Methods: The purpose of this retrospective study was to compare the survival times of cats with NLSA treated with radiation therapy (RT) alone, chemotherapy alone, or RT 1 chemotherapy and identify potential prognostic variables that affected survival. Cats were grouped according to therapy: RT 1 chemotherapy (n 5 60), RT alone (n 5 19), or chemotherapy alone (n 5 18).Results: Survival was calculated with 2 methods. The 1st survival analysis (method A) included all cats, but counted only deaths caused by progressive NLSA. The median survival time (MST), regardless of therapy modality, was 536 days. The 2nd survival analysis (method B) also included all cats and counted all deaths, regardless of cause, as events. The overall MST calculated for all deaths was 172 days. A negative independent prognostic variable identified was anemia (P o .001), and positive independent prognostic variables were a complete response to therapy (P o .001) and total radiation dose 432 Gy (P 5 .03).Conclusions and Clinical Importance: There were no significant differences in survival times among the 3 treatment groups but these results suggest that the addition of higher doses of RT to a cat's treatment protocol may control local disease and therefore influence survival.

Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the doselimiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received z2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 F 6.17 ng/mg tissue. Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.Liposome-encapsulated chemotherapy was developed to improve selectivity of drug for tumor compared with normal tissue. Despite the achievement of tumor drug levels that are up to 10-fold higher than those achieved with unencapsulated drugs, particularly when given concurrently with hyperthermia, clinical efficacy of these agents has been only modestly improved (1 -4). Decreased toxicity, in particular the cardiotoxicity seen with doxorubicin, has been the most significant benefit derived from these formulations.One potential explanation for the lack of clinical benefit from liposomal drug delivery to the tumor tissue is the dependence of cytotoxicity on the presence of free drug. Although the liposomes may accumulate preferentially in tumors, the mechanisms by which traditional liposomes release their contents are not well understood (5). The development of liposomes engineered for triggered drug release is one approach that addresses this problem directly.The development of hyperthermia-mediated drug release from liposomes was first reported in 1978 (6). These early thermosensitive liposomes typically released their contents at temperatures > 42jC. Temperatures in this range are difficult to achieve uniformly in a clinical setting. In addition, drug release was slow, requiring 30 minutes to release 40% of the contents (7). Because of...

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Purpose:To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. Experimental Design: 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2-5 CEM43jCT90) or high (20-50 CEM43jCT90) thermal dose in combination with radiotherapy. Most dogs (90%) received four to six hyperthermia treatments over 5 weeks. Results: In the primary analysis, median (95% confidence interval) duration of local control in the low-dose group was1.2 (0.7-2.1) years versus1.9 (1.4-3.2) years in the high-dose group (log-rank P = 0.28). The probability (95% confidence interval) of tumor control at 1 year in the low-dose versus high-dose groups was 0.57 (0.43-0.70) versus 0.74 (0.62-0.86), respectively. Using multivariable procedure, thermal dose group (P = 0.023), total duration of heating (P = 0.008), tumor volume (P = 0.041), and tumor grade (P = 0.027) were significantly related to duration of local tumor control. When correcting for volume, grade, and duration of heating, dogs in the low-dose group were 2.3 times as likely to experience local failure. Conclusions: Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription.

We envision that CaWO4 (CWO) nanocrystals have the potential for use in biomedical imaging and therapy because of the unique ways this material interacts with high energy radiation (Figure 1). These applications, however, require development of nanoparticle (NP) formulations that are suitable for in vivo applications; primarily, the formulated nanoparticles should be sufficiently small, chemically and biologically inert, and stable against aggregation under physiological conditions. The present study demonstrates one such method of formulation, in which CWO nanoparticles are encapsulated in bio-inert block copolymer (BCP) micelles. For this demonstration, we prepared three different CWO nanocrystal samples having different sizes (3, 10 and 70 nm in diameter) and shapes (elongated vs. truncated rhombic). Depending on the specific synthesis method used, the as-synthesized CWO NPs contain different surfactant materials (citric acid, cetyl trimethylammonium bromide, or a mixture of oleic acid and oleylamine) in the coating layers. Regardless of the type of surfactant, the original surfactant coating can be replaced with a new enclosure formed by BCP materials using a solvent exchange method. Two types of BCPs have been tested: poly(ethylene glycol-block-n-butyl acrylate) (PEG-PnBA), and poly(ethylene glycol-block-D,L-lactic acid) (PEG-PLA). Both BCPs are able to produce fully PEGylated CWO NPs that are stable against aggregation under physiological salt conditions for very long periods of time (for at least three months). The optical and radio-luminescence properties of both BCP-encapsulated and surfactant-coated CWO NPs were extensively characterized. The study confirms that the BCP coating structure does not influence the luminescence properties of CWO NPs.