Median Survival Time Of Animals Research Articles

A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma.

Metastatic melanoma can be difficult to detect until at the advanced state that decreases the survival rate of patients. Several FDA-approved BRAF inhibitors have been used for treatment of metastatic melanoma, but overall therapeutic efficacy has been limited. Lutetium-177 (177 Lu) enables simultaneous tracking of tracer accumulation with single-photon emission computed tomography and radiotherapy. Therefore, the codelivery of 177 Lu alongside chemotherapeutic agents using nanoparticles (NPs) might improve the therapeutic outcome in metastatic melanoma. Cellulose nanocrystals (CNC NPs) can particularly deliver payloads to lung capillaries in vivo. Herein, 177 Lu-labeled CNC NPs loaded with vemurafenib ([177 Lu]Lu-CNC-V NPs) is developed and the therapeutic effect in BRAF V600E mutation-harboring YUMM1.G1 murine model of lung metastatic melanoma is investigated. The [177 Lu]Lu-CNC-V NPs demonstrate favorable radiolabel stability, drug release profile, cellular uptake, and cell growth inhibition in vitro. In vivo biodistribution reveals significant retention of the [177 Lu]Lu-CNC-V NPs in the lung, liver, and spleen. Ultimately, the median survival time of animals is doubly increased after treatment with [177 Lu]Lu-CNC-V NPs compared to control groups. The enhanced therapeutic efficacy of [177 Lu]Lu-CNC-V NPs in the lung metastatic melanoma animal model provides convincing evidence for the potential of clinical translation for theranostic CNC NP-based drug delivery systems after intravenous administration.

P11.24 CR13626, an oral tyrosine kinase inhibitor crossing the blood brain barrier, reduces tumour growth and prolongs survival in a mouse model of glioblastoma

Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in GBM etiopathogenesis. Currently there is no cure for GBM. Tumour heterogeneity and the presence of the blood brain barrier (BBB), with efflux transporters, are some of the causes of failure of novel therapeutic agents. Thus, appropriate target selectivity and pharmacokinetics (including brain penetration) are critical issues for the generation of potential drug candidates. The main in-vitro and in-vivo properties and antitumour activity of CR13626, a novel brain penetrant TK inhibitor, are presented. MATERIAL AND METHODS CR13626 inhibitory activity against a panel of 173 kinases was assessed. The effect on cellular proliferation was verified in different 2D human glioblastoma cell lines (U87MG, U373, U87MG vIII) and in a U87MG 3D spheroid model by ViaCount assays. The in-vivo antitumour activity was determined in a mouse model of glioblastoma based on the orthotopic injection of U87MG-Luciferase GBM cells in nude mice: oral treatment started on day 9 post-implantation and continued for 10 days (50 mg/kg/daily). Tumour progression was evaluated through the measurement of bioluminescence (BLI) at the end of dosing (day 19) and during follow-up (day 26–33). Survival was also monitored. The pharmacokinetics and brain exposure of CR13626 were assessed by LC/MS/MS in plasma and brain homogenate tissues of CD1 and tumour-bearing nude mice. RESULTS CR13626 potently inhibited FYN, YES, KDR and EGFR kinases, relevant for GBM development, with IC50 values of 69 nM, 3.6 nM, 82 nM and 6 nM, respectively. The compound reduced the proliferation of different human glioblastoma cell lines (GI50 1–3 µM). In CD1 mice, CR13626 had a good oral bioavailability (72%) and brain penetration (brain/plasma ratio of 1.4). In-vivo BLI analysis indicated a time-dependent reduction of tumour growth, reaching 60% on the last BLI evaluation 33 days post-implantation (i.e. 15 days after the end of dosing). Tumour growth inhibition translated into an increase of 25% of the median survival time of animals treated with CR13626 compared to the vehicle group (p<0.05). The observed antitumour effects agreed with the exposure of tumour-bearing mice to CR13626, which was above the TKs in-vitro IC50 values. CONCLUSION The combined abilities of CR13626 to inhibit the activity of TKs involved in GBM development, to cross the BBB, and to reduce tumour growth in-vivo leading to increased survival, warrant its further development as a drug candidate in GBM.

Development of a magnetic nano-graphene oxide carrier for improved glioma-targeted drug delivery and imaging: In vitro and in vivo evaluations

To overcome the obstacles inflicted by the BBB in Glioblastoma multiforme (GBM) we investigated the use of Multifunctional nanoparticles that designed with a Nano-graphene oxide (NGO) sheet functionalized with magnetic poly (lactic-co-glycolic acid) (PLGA) and was used for glioma targeting delivery of radiosensitizing 5-iodo-2-deoxyuridine (IUdR). In vitro biocompatibility of nanocomposite has been studied by the MTT assay. In vivo efficacy of magnetic targeting on the amount and selectivity of magnetic nanoparticles accumulation in glioma-bearing rats under an external magnetic field (EMF) density of 0.5 T was easily monitored with MRI. IUdR-loaded magnetic NGO/PLGA with a diameter of 71.8 nm, a zeta potential of −33.07 ± 0.07 mV, and a drug loading content of 3.04 ± 0.46% presented superior superparamagnetic properties with a saturation magnetization (Ms) of 15.98 emu/g. Furthermore, Prussian blue staining showed effective magnetic targeting, leading to remarkably improved tumor inhibitory efficiency of IUdR. The tumor volume of rats after treatment with IUdR/NGO/SPION/PLGA + MF was decreased significantly compared to the rats treated with buffer saline, IUdR and SPION/IUdR/NGO/PLGA. Most importantly, our data demonstrate that IUdR/NGO/SPION/PLGA at the present magnetic field prolongs the median survival time of animals bearing gliomas (38 days, p < 0.01). Nanoparticles also had high thermal sensitivities under the alternating magnetic field. In conclusion, we developed magnetic IUdR/NGO/PLGA, which not only achieved to high accumulation at the targeted tumor site by magnetic targeting but also indicated significantly enhanced therapeutic efficiency and toxicity for glioma both in vitro and in vivo. This innovation increases the possibility of improving clinical efficiency of IUdR as a radiosensitizer, or lowering the total drug dose to decrease systemic toxicity.

PH-Sensitive star-shaped poly(glutamic acid) with a porphyrin core as highly efficient photosensitizers for photodynamic therapy and molecular imaging

Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CB2R-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CB2R- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects.Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.

Multilayer photodynamic therapy for highly effective and safe cancer treatment.

Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.

Clinical Outcome for MCTs of Canine Pinnae Treated with Surgical Excision (2004–2008)

Canine mast cell tumors (MCTs) are the most common cutaneous neoplasm in the dog. It has been suggested that MCT in certain locations may behave in a more biologically aggressive fashion than MCTs located in others; however, no published data are available for MCTs of canine pinnae treated with surgical excision. A retrospective study of 28 animals with surgical excision of MCTs of pinnae was completed with a medical record review and follow-up questionnaire to the operating veterinarian. The effect of tumor grade, clean or dirty excision, cartilage penetration, and mitotic index (MI) on local recurrence and survival time (ST) was evaluated. There was local recurrence in one dog with a grade 2 MCT and in seven of eight dogs with grade 3 MCTs. The median ST of animals with grade 1 and 2 MCTs was not reached, whereas the median ST of animals with grade 3 MCTs was 10 mo. There was no statistical association between histologically clean and dirty margins and either local recurrence or ST. A prolonged disease free interval without local recurrence may be achieved with local excision of grade 1 and 2 MCTs. Animals with grade 3 MCTs had a uniformly poor outcome with short times to local recurrence and death.

Low-dose conventional chemotherapeutics synergizes with dendritic cell - based immunotherapy in antitumor activity

Event Abstract Back to Event Low-dose conventional chemotherapeutics synergizes with dendritic cell - based immunotherapy in antitumor activity Alexander Gorbach1*, Natalia Khranovska2, Vladimir Pozur1, Oksana Skachkova2, Natalia Svergun2, Roman Sydor1 and Viktoria Nikulina1 1 Kyiv National Taras Shevchenko University, Educational and Scientific Centre «Institute of Biology», Ukraine 2 National Cancer Institute of the Ministry of Public Health of Ukraine, Ukraine Background. The benefit of combining low-dose chemotherapeutics with cancer vaccine therapy has not been established. Here we investigated the antitumor effect of conventional chemotherapeutics cyclophosphamide (CP) or doxorubicin (DOX), or cisplatin (CIS) in combination with DC-based immunotherapy in murine tumor models. Methods. Studies have been performed with 100 C57Bl/6 and 213 CBA mice with lethal dose of Lewis lung carcinoma (LLC) or sarcoma 37 (S37) respectively. DCs loaded with mechanoactivated lyophilized tumor cells have been used as immunotherapy agent. DCs were administered i/v three times with two-day interval. Low-dose chemotherapeutics were administered in “metronomic” regimen before DC-immunotherapy. Results. Addition of CP improved DC-immunotherapy leading to a significant decrease in the number and volume of metastases in lungs. Combination of DC-immunotherapy with DOX or CIS significantly improved median survival time of animals with S37 in comparison with control group. Metronomic chemotherapy resulted in a significant reduction in the proportions of T-reg cells and mRNA levels of immunosuppressive cytokines in the peripheral blood and lymph nodes lymphocytes. Addition of chemotherapeutics to DC-immunotherapy also augments Th-1 immune response, increases number of activated CD69+, CD54+, CD25+ splenocytes, enhance spleen macrophages phagocyte activity and reactive oxygen species (ROS) production, cytotoxic activity of NK-cells and CTL (p<0,05). Antitumor effectiveness of DC-immunotherapy combined with low-dose chemotherapeutics are associated with significant decrease in mRNA levels of TGF-β, VEGF, IL-10 in the residual tumor sites. Conclusions. Low-dose chemotherapeutics enhance the antitumor effect of DC-based immunotherapy. These findings form the basis to a new multimodality treatment in cancer patients. Keywords: Dendritic Cells, Doxorubicin, Cisplatin, Cyclophosphamide, Immunotherapy Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Gorbach A, Khranovska N, Pozur V, Skachkova O, Svergun N, Sydor R and Nikulina V (2013). Low-dose conventional chemotherapeutics synergizes with dendritic cell - based immunotherapy in antitumor activity. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00151 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mr. Alexander Gorbach, Kyiv National Taras Shevchenko University, Educational and Scientific Centre «Institute of Biology», Kyiv, 01601, Ukraine, horbach.alex@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alexander Gorbach Natalia Khranovska Vladimir Pozur Oksana Skachkova Natalia Svergun Roman Sydor Viktoria Nikulina Google Alexander Gorbach Natalia Khranovska Vladimir Pozur Oksana Skachkova Natalia Svergun Roman Sydor Viktoria Nikulina Google Scholar Alexander Gorbach Natalia Khranovska Vladimir Pozur Oksana Skachkova Natalia Svergun Roman Sydor Viktoria Nikulina PubMed Alexander Gorbach Natalia Khranovska Vladimir Pozur Oksana Skachkova Natalia Svergun Roman Sydor Viktoria Nikulina Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Augmented Antitumor Activity against B-Cell Lymphoma by a Combination of Monoclonal Antibodies Targeting TRAIL-R1 and CD20

Mapatumumab and lexatumumab are fully humanized, high-affinity immunoglobulin G(1 lambda) monoclonal antibodies (mAb) that target/activate the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2), respectively, triggering the extrinsic apoptotic pathway. Theoretically, synergistic antitumor activity should be observed by combining TRAIL-R mAbs with agents (e.g., rituximab) that activate the intrinsic apoptotic pathway. To this end, targeted antigen expression in a NHL-cell panel was evaluated by flow cytometry. NHL cells were exposed to mapatumumab or lexatumumab followed by rituximab, isotype, or RPMI. DNA synthesis was quantified by [(3)H]-thymidine incorporation assays. Induction of apoptosis was detected by flow-cytometric analysis. For antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) studies, standardized (51)Cr-release assays were done. We inoculated severe combined immunodeficiency (SCID) mouse with Raji cells i.v. The animals then were treated with various combinations of rituximab, mapatumumab, lexatumumab, and isotype alone or in combination. In vitro exposure to mapatumumab resulted in significant apoptosis (30-50%) and decreased DNA synthesis in sensitive lymphoma cells. Mapatumumab/rituximab combination resulted in a significant inhibition of cell proliferation (90% reduction) when compared with mapatumumab (60% reduction) or rituximab (5% reduction). In vivo, the median survival time of animals treated with mapatumumab and rituximab was longer (not reached) than those treated with rituximab monotherapy [33 days (95% confidence interval, 29-37), log-rank test, P = 0.05]. Mapatumumab induces apoptosis, cell growth arrest, ADCC, and CMC. The combination of mapatumumab plus rituximab is more effective in controlling lymphoma growth in vivo than either antibody. Rituximab and mapatumumab warrant further evaluation against B-cell lymphoma.

JAA-F11

JAA-F11 antibody (Ab) is a monoclonal Ab that is specific for the Thomsen–Friedenreich antigen, Galβ1-3GalNAcα (TF-Ag). TF-Ag, discovered in the late 1920s, is a tumor-associated carbohydrate Ag of many clinically widespread carcinomas. In a mouse model, JAA-F11 Ab significantly extended median survival time of animals with metastatic 4T1 breast tumors and caused > 50% inhibition of lung metastasis. 124Iodine labeled JAA-F11 Ab in in vivo micro positron emission tomography showed tumor specificity in a mouse breast tumor model, with no preferential uptake by any other organ. Human cancer cell adhesion to vascular endothelium was also blocked by JAA-F11. Structural specificity of the Ab was shown with glycan array analysis and indicated that this Ab, unlike many other Abs to TF-Ag, will not bind to a related glycolipid on natural killer cells, kidney or spleen. Patients with higher levels of naturally occurring anti-TF-Ag Ab appear to have a better prognosis, indicating that passive transfer of JAA-F11 or active immunization, resulting in production of anti-TF-Ag Ab, would clinically be beneficial for the patient.

Inhibition of Spontaneous Breast Cancer Metastasis by Anti—Thomsen-Friedenreich Antigen Monoclonal Antibody JAA-F11

Thomsen-Friedenreich antigen (TF-Ag) is expressed in many carcinomas, including those of the breast, colon, bladder, prostate. TF-Ag is important in adhesion and metastasis and as a potential immunotherapy target. We hypothesized that passive transfer of JAAF11, an anti -TF-Ag monoclonal antibody, may create a survival advantage for patients with TIF-Ag -expressing tumors by cytotoxicity, blocking of tumor cell adhesion, inhibition of metastasis. This was tested using in vitro models of tumor cell growth; cytotoxicity assays; in vitro, ex vivo, in vivo models of cancer metastasis; and, finally, in vivo effects in mice with metastatic breast cancer. Unlike some anti-TF-Ag antibodies, JAA-F11 did not enhance breast carcinoma cell growth. JAA-F11 did not induce the killing of 4T1 tumor cells through complement-dependent cytotoxicity or apoptotic mechanisms. However, JAA-F11 blocked the stages of metastasis that involve the adhesion of human breast carcinoma cells to human endothelial cells (human umbilical vein endothelial cells and human bone marrow endothelial cells 60) in in vitro static adhesion models, in a perfused ex vivo model, in murine lung vasculature in an in vivo metastatic deposit formation assay. JAA-F11 significantly extended the median survival time of animals bearing metastatic 4T1 breast tumors and caused a > 50% inhibition of lung metastasis.

Use of thoracoscopy to determine the etiology of pleural effusion in dogs and cats: 18 cases (1998-2001).

To assess use of thoracoscopy to determine causes of pleural effusion in dogs and cats. Retrospective study. 15 dogs and 3 cats with pleural effusion. Medical records were reviewed from 1998 to 2001 for dogs and cats that had exploratory thoracoscopy, biopsy, and histologic analysis to determine the etiology of pleural effusion. Intraoperative and postoperative complications were recorded. Surgical biopsy specimens were evaluated for quantity and quality for providing a histologic diagnosis. Biopsy specimens were deemed adequate in quantity and quality to render a histologic diagnosis in all animals. Etiology of the effusion was neoplasia in 8 animals and non-neoplastic pleuritis in 10 animals. Median survival time of animals with neoplasia was 15 days, whereas those with inflammatory diseases had median survival time of > 785 days. Postoperative pneumothorax was encountered in 2 animals subsequent to pulmonary biopsy. No other major complications were recorded. Thoracoscopy is a diagnostic option that provides excellent viewing of intrathoracic structures and adequate biopsy specimens with minimal complications. This technique provides a less invasive alternative to thoracotomy for evaluating the etiology of pleural effusion.

Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain

Purpose: Radiosurgery refers to the delivery of high, single focused beams of ionizing radiation to defined intracranial lesions. 1,3 Bis[2-chloroethyl]-1-nitrosourea (BCNU) and cis-diammine-1,1-cyclobutane-dicarboxylate platinum (II) (carboplatin) are commonly used cytotoxic agents for the treatment of malignant gliomas of the brain. Drug therapies have exhibited a modest enhanced cell killing when combined with radiation in experimental animal tumor systems. The purpose of the present study was to investigate the role of cytotoxic drugs, such as BCNU and carboplatin, in combination with a single high dose of radiosurgery on the tumor control rates of 9L tumors in the rat brain. Methods and Materials: Combined radiosurgery (25 Gy single dose) and/or chemotherapy (a single dose of BCNU, 7 mg/kg, i.p. 1.5 or 16 h prior to or 16 h after irradiation or a single dose of carboplatin, 30 mg/kg, administered either 1 h or 4 h prior to irradiation) was delivered 12 days after stereotactic tumor implantation. For dose escalation study, 4–10 mg/kg of BCNU was used. Results: The radiation alone group showed a dose-dependent survival. A single dose of 25 Gy to the control group resulted in an increase of the median survival time from 20 days to 42 days, but all animals died of the tumor in 50 days. A significant prolongation of the median survival time of animals was more than 100 days, resulting in animal cures of 50% or more when combined with radiosurgery (25 Gy) and BCNU (7 mg/kg). BCNU alone did not prolong the median survival time of the animal with the 9L brain tumor. In contrast, there was no survival improvement when the animals were treated with combined radiosurgery and carboplatin. None of the long-term surviving animals showed any significant brain tissue damage as evaluated by histopathology and clinical observations. Conclusion: The data clearly suggest that the combined modalities of radiosurgery and concomitant BCNU represent an effective therapeutic regimen in the treatment of radioresistant human malignant gliomas of the brain. This study represents the first experimental report of the effectiveness of combined chemotherapy and radiosurgery.

Inhibitory Effect of a CD4-CDR3 Peptide Analog on Graft-Versus-Host Disease Across a Major Histocompatibility Complex-Haploidentical Barrier

A structure-based designed peptide has been engineered to exhibit the same molecular surface as a portion of the CDR3-like region in domain 1 of the murine CD4 molecule. Earlier in vitro experiments indicated that this analog, known as rD-mPGPtide, inhibited T-cell proliferation in mixed lymphocyte reactions and blocked activation of both normal CD4+ T cells and T-cell lines after T-cell receptor triggering. In addition, rD-mPGPtide proved to be a potent inhibitor in vivo of CD4+ T-cell-mediated experimental allergic encephalomyelitis disease in the SJL mouse model. In this current report, we have evaluated the potential of rD-mPGPtide for suppressing the development of graft-versus-host disease (GVHD) in an irradiated major histocompatibility complex (MHC)-haploidentical murine bone marrow transplantation (BMT) model [(B6 x DBA/2)F1-->(B6 x CBA)F1 (950 cGy)]. Our results indicated that early administration of rD-mPGPtide was effective in the inhibition of alloreactive responses of the donor T cells against the host and thus delayed or prevented the onset of GVHD. The median survival time of animals treated with rD-mPGPtide was enhanced as much as four-fold with as little as a single dose of peptide at the time of transplant. Decreased alloreactivity was indicated by phenotypic and functional analysis of positively selected thoracic duct lymphocytes 4 days after transplant and by histopathological examination of skin and gastrointestinal tissue samples 4 weeks later. Therefore, the administration of a CD4-CDR3 peptide is an efficacious approach against the development of GVHD during allogeneic BMT.

Combined treatment of a solid tumour by local hyperthermia and actionomycin D.

(BALB/c X C57BL/6)F1 mice bearing an SV-40 fibrosarcoma in the limb were injected with 0.045, 0.09 and 0.18 microgram/g body wt actinomycin D into the tumour. Similar animals were also treated with local hyperthermia (39.7 degrees, 42.3 degrees and 43.6 degrees C intratumour temperature for 30 min). The marked increase in median survival time following the combination of drug and local hyperthermia indicates that the combined treatment has a synergistic effect in the control of solid tumours. The median survival time of animals receiving the two treatments in immediate succession was higher than in animals with 30 min between treatments. This has important implications for the therapy of human cancer.

Immunotherapy with Neuraminidase-Treated Tumor Cells after Radiotherapy

SONG, C. W., AND LEVITT, S. H., Immunotherapy with Neuraminidase-Treated Tumor Cells after Radiotherapy. Radiat. Res. 64, 485-491 (1975). The effect of active immunotherapy with Vibrio cholerae neuraminidase-treated syngeneic tumor cells (VCN-cells) following radiotherapy has been studied with 3methylcholanthrene-induced fibrosarcoma, M-79, transplanted to the thigh of C3H/HeJ mice. When the tumors reached 4-8 mm in diameter, various treatments were started. X-irradiation with 2000 rad in a single dose induced a complete regression of 24 out of 103 tumors (23.3%). The inoculation of 1 X 106 of VCN-cells to the tumor-bearing animals, every other day for a total of three doses, caused a complete regression of 6 out of 57 tumors (10.5%). Treatments of animals with the immunotherapy starting 1 day after X-irradiation of tumors with 2000 rad resulted in a complete regression of 22 out of 58 tumors (37.9%). The median survival time of animals that received combined radiotherapy and immunotherapy was longer than that observed after either treatment alone.

The prognosis following the surgical excision of canine mammary neoplasms

Three hundred and twenty bitches from which mammary neoplasms had been excised were followed up until death, or for at least 2 years post surgery. The median survival time of animals with histologically benign tumours was at least 114 weeks, whilst for dogs with carcinomas it was 70 weeks. Only 43% of dogs with carcinoma eventually died as a result of the tumour but a more accurate prognosis was possible by subdividing these tumours into their different morphological types. Animals with solid and anaplastic carcinomas had a significantly poorer survival time than those with papillary or tubular carcinomas. Other valuable prognostic aids included histological evidence of infiltration of the surrounding tissues by tumour cells in the case of tubular and solid carcinomas, and the volume of the tumour at excision. Canine mammary tumours may be of value as models to study the effect of various types of post surgical therapy, and particularly immunotherapy. The observation that most tumours which are destined to kill the host do so within one year of surgery indicates that evaluation of results will be possible much sooner than could be expected from human clinical trials.