Evaluation of ifosfamide for treatment of various canine neoplasms

lfosfamide (3-[2-chloroethyl]-2[(2 chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide) is an alkylating agent with a broad spectrum of antitumor activity. The efficacy and toxicity of ifosfamide were evaluated in 72 dogs with spontaneously occurring tumors. Forty dogs (56%) had lymphoma, 31 (43%) had sarcomas, and 1 had a metastatic carcinoma. Five dogs received ifosfamide at dosages <350 mg/m2 IV. Neither toxicity nor response were observed, and the remaining dogs received ifosfamide at 350 mg/m2 (n = 18) and 375 mg/m2 body surface area IV (n = 49). Saline diuresis and the thiol compound mesna were used to prevent urothelial toxicity. Fifty-two dogs had measurable tumors and could be evaluated for response. Complete responses were seen in 1 dog with metastatic leiomyosarcoma of the urinary bladder and in 1 dog with metastatic cutaneous hemangiosarcoma. One dog with lymphoma had a partial response for 112 days. Six dogs with splenic hemangiosarcoma received ifosfamide postsplenectomy and their median survival time was 147 days. The acute dose limiting toxicity was neutropenia 7 days after administration of ifosfamide. The median and mean neutrophil counts 7 days after ifosfamide at 350 mg/m2 were 2,035 cells/microL and 4,773 cells/microL, respectively (n = 12). The median and mean neutrophil counts 7 days after ifosfamide at 375 mg/m2 were 2,500 cells/microL and 3,594 cells/microL, respectively (n = 37). No dog developed clinical or microscopic evidence of hemorrhagic cystitis. Ifosfamide appears safe to use in tumor-bearing dogs, and the evaluation of combination chemotherapy protocols that include ifosfamide should be considered.     

Doxorubicin and BAY 12-9566 for the treatment of osteosarcoma in dogs: a randomized, double-blind, placebo-controlled study

BACKGROUND: This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy. HYPOTHESIS: Survival will be prolonged in dogs receiving BAY 12-9566. ANIMALS: The study included 303 dogs with appendicular osteosarcoma. METHODS: Dogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12-9566; 4-[4-4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy. RESULTS: Median survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12-9566 did not influence survival. Multivariate analysis revealed that increasing age (P = .004), increasing weight (P = .006), high serum alkaline phosphatase (ALP) (P = .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P = .013), and as plasma active MMP-2 concentrations increased (P = .027), the risk of dying increased. CONCLUSIONS AND CLINICAL IMPORTANCE: Doxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma.     

Microalbuminuria is not associated with cisplatin-induced azotemia in dogs

BACKGROUND: Cisplatin is an effective antineoplastic agent but its use is limited by renal toxicity. Microalbuminuria is a marker of renal damage and might be an indicator of cisplatin-induced azotemia. NULL HYPOTHESIS: Microalbuminuria is not associated with azotemia in dogs treated with cisplatin. ANIMALS: This study used 32 client-owned dogs. METHODS: This was a prospective observational study in which cancer-bearing dogs were treated with cisplatin chemotherapy. Cisplatin-induced azotemia was defined as an increase of serum creatinine concentration above the reference range. Serum creatinine concentration, other routine tests of renal function, and microalbuminuria were measured after each cisplatin treatment. Variables potentially associated with azotemia were compared by use of Fisher's exact test and Wilcoxon's rank-sum test. RESULTS: Cisplatin-induced azotemia occurred in 10 (31%) dogs after 1-5 treatments. At each of the first 3 treatments, the proportions of dogs with microalbuminuria were similar between dogs with and without azotemia. CONCLUSIONS AND CLINICAL IMPORTANCE: Microalbuminuria measured after each treatment was not associated with azotemia through the first 3 treatments. Testing for microalbuminuria as a marker for cisplatin-induced renal damage is insensitive and not recommended.     

Evaluation of a novel tumor vaccine in dogs with hemangiosarcoma

BACKGROUND: Hemangiosarcoma (HSA) is a highly metastatic and often rapidly fatal tumor of dogs. At present, adjuvant chemotherapy is the only proven effective treatment for dogs with HSA, though the benefits from chemotherapy are modest. Administration of immunotherapy together with chemotherapy has also been reported to improve survival in dogs with HSA. Therefore, we evaluated safety and immunologic responses to a novel tumor vaccine administered together with doxorubicin chemotherapy in dogs with different stages of HSA. HYPOTHESIS: That tumor vaccination could be safely and effectively combined with doxorubicin chemotherapy for treatment of dogs with HSA. ANIMALS: Twenty-eight dogs with various stages of HSA were enrolled in the study. METHODS: The HSA vaccine was prepared with lysates of allogeneic canine HSA cell lines mixed with an adjuvant composed of liposome-DNA complexes. Dogs received a series of 8 immunizations administered over a 22-week period, and most also received chemotherapy. Clinical adverse effects were noted, immune responses were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, and survival times were calculated. RESULTS: The most common adverse effects observed in vaccinated dogs also treated with doxorubicin chemotherapy were diarrhea and anorexia. Vaccinated dogs were found to mount strong humoral immune responses against a control antigen and, most dogs also mounted antibody responses against canine HSA cells. Thirteen dogs with stage II splenic HSA that received the tumor vaccine plus doxorubicin chemotherapy had an overall median survival time of 182 days. CONCLUSIONS: We conclude that an allogeneic tumor lysate vaccine is safe in dogs with HSA and can elicit humoral immune responses in dogs that are receiving concurrent doxorubicin chemotherapy.     

Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma

BACKGROUND: Various chemotherapy protocols for treating lymphoma in dogs have been published; however, comparison of protocols from different studies is difficult, especially when evaluating survival time and toxicoses. HYPOTHESIS: The choice of COAP (C, cyclophosphamide; O, vincristine; A, cytosine arabinoside; P, prednisone) and a modified University of Wisconsin 19-week (UW-19) induction protocol has no influence on overall survival times in dogs with lymphoma. ANIMALS: One hundred and one dogs with multicentric lymphoma. METHODS: Retrospective study (2001-2006). Dogs induced with either an 8-week COP-based protocol (C, cyclophosphamide; O, vincristine; and P, prednisone) with maintenance therapy (COAP group) or a 19-week CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisone) based protocol (UW-19 group) were compared in terms of the duration of first remission, survival time, toxicoses, and cost. RESULTS: There were 71 dogs in the COAP group and 30 dogs in the UW-19 group. Various protocols were used after the first relapse. The median duration of the first remission for the COAP and UW-19 groups were 94 days (range, 6-356 days) and 174 days (28-438 days), respectively (P < .01). The median survival times for dogs in the COAP and UW-19 groups were 309 days (6-620 days) and 275 days (70-1102+ days), respectively (P = .09). Dogs in the COAP group had a hazard ratio of 1.9 (95% CI 1.1-3.4) for death relative to the UW-19 group (P = .03), after controlling for the confounders (World Health Organization clinical stage, age, sex, use of doxorubicin during reinduction). The severity of neutropenia and gastrointestinal toxicoses were significantly higher in the UW-19 group than in the COAP group (P = .01 and P < .01, respectively). CONCLUSION AND CLINICAL IMPORTANCE: Use of a long-term doxorubicin-containing sequential combination chemotherapy protocol is associated with a decreased risk of relapse and death relative to a non-doxorubicin-containing protocol.     

Inter‐ and intra‐specific interactions affecting crustacean trap fisheries—Implications for management

The UK coastal trap fisheries target two key species, European lobster Homarus gammarus (L.) and brown crab Cancer pagurus L. Their stock status is assessed periodically using size‐based, yield‐per‐recruit analysis. Fishery trends are described using landings and, where available, effort data to estimate catch per unit of effort (CPUE), nominally proportional to abundance. Despite being caught together, assessments assume that concurrent capture of these species does not distort their individual CPUE estimates. Here, an in situ experiment tested impacts of inter‐specific and intra‐specific interactions by pre‐loading baited traps with different species and observing subsequent catches. Pre‐loaded European lobster significantly reduced brown crab catches, whereas, other species produced no such effects. The findings highlight the likely inconsistency of using CPUE as an index of abundance if landings data originate from a mixed‐species fishery in which species interactions and targeting behaviour of fishers are unknown or un‐quantified.     

Screening of differentially expressed genes in colorectal cancer based on TCGA database and verification of novel gene CCDC78

AIM To explore novel genes closely related to the prognosis of colorectal cancer through bioinformatics analysis of RNA sequencing (RNA-Seq） data of gene expression profile in large samples of colorectal cancer tissues from The Cancer Genome Atlas (TCGA) database, and to validate the new genes and study their functions. METHODS The RNA-Seq data were downloaded from TCGA database to screen differentially expressed genes, R-survival package was used to carry out survival analysis of differentially expressed genes to screened out genes related to prognosis of colorectal cancer, and the most significantly up-regulated genes that have not been reported in cancer studies were selected for further verification. RT-qPCR was employed to detect mRNA expression of these novel genes in human colon cancer cell lines and human colorectal cancer tissues. The colon cancer cell line with stable silencing of the novel gene expression was constructed by transfection of lentivirus vector, and its viability, migration and invasion were detected by CCK-8 assay and Transwell assay. RESULTS (1) A total of 4 017 differentially expressed genes were found in the gene expression profile of the colorectal cancer samples. Kaplan-Meier survival analysis showed that 69 genes were closely related to poor prognosis in patients with colorectal cancer, 36 of which were up-regulated, and 11 of these 36 genes have not been reported in cancer studies. (2) The mRNA expression of the top 3 up-regulated genes CCDC78, PGGHG and TSPEAR of the 11 genes was significantly increased in colon cancer cell lines, and the expression of CCDC78 mRNA was also up-regulated in colorectal cancer tissues. (3) CCDC78 gene silencing significantly suppressed the viability, migration and invasion of colon cancer cells (P<0.01). CONCLUSION Bioinformatics analysis based on TCGA database is helpful to discover nov?el genes related to prognosis of colorectal cancer, and CCDC78 may be a novel oncogene associated with poor prognosis of colorectal cancer.     

The Prognostic Significance of Angiogenesis in Canine Mammary Tumors

The purpose of the study was to determine if neovascularization, a measure of angiogenesis, is correlated with metastasis of mammary tumors in dogs. Forty-six paraffin-embedded tissue blocks of benign and malignant canine mammary tumors obtained from 42 clinical cases at the Iowa State University Veterinary Teaching Hospital were retrieved from the archives of the Department of Veterinary Pathology. Of the dogs with malignant tumors, cases with and without lymph node metastasis were chosen. Neovascularization was quantified by light microscopy on formalin-fixed, paraffin-embedded sections of canine mammary tumors using an avidin biotin immunoperoxidase assay for factor VIII-related antigen. Mean microvessel counts for each group were statistically evaluated using analysis of variance. The mean number of microvessels was highest in the malignant tumors of dogs with lymph node metastasis (44). This number was significantly different from the mean number of microvessels in the benign tumors (28; P = .03) and a trend occurred toward higher microvessel counts in malignant tumors with lymph node metastasis versus malignant tumors of dogs without metastasis (32; P = .1). No significant difference was found between the number of microvessels found in malignant tumors without metastasis versus benign tumors. The trend toward higher microvessel counts in mammary tumors that have metastasized supports the premise that angiogenesis may be an independent and significant prognostic indicator in dogs with malignant mammary tumors, as it is in women with breast cancer.     

血清中新型癌症生物标记物——miRNA

MicroRNA(miRNA)是一类长度约22 nt的非编码单链RNA,广泛存在于动物、植物中,具有基因表达调控的功能。研究表明,miRNA的异常表达与人类的各种癌症相关,且miRNA可作为肿瘤抑制基因或癌基因存在。当前许多研究集中在生理学或病理学过程miRNA表达的研究,血清中miRNA可作为检测各类癌症与疾病的潜在生物标记物用于病人外周血癌症的早期检测与癌症复发的检测。血清miRNA的差异表达对癌症的研究具有较大的前景。     

Prognostic Value of Argyrophilic Nucleolar Organizer Region (AgNOR) Staining in Feline Intestinal Lymphoma

Limited information is available on prognostic factors for cats with lymphoma. The quantity of argyrophilic nucleolar organizer region (AgNOR) proteins can be used as a measurement of cellular proliferative activity. To determine if AgNORs were of prognostic value for feline intestinal lymphoma, the silver staining technique was performed on paraffin-embedded sections of 31 cases. Mean number of AgNORs per nucleus ranged from 1.02 to 4.32. Twenty-four (78%) cats had small AgNORs and 7 (22%) had large AgNORs. All cats were treated identically with a combination chemotherapy protocol. Response to chemotherapy was 87%. Median remission duration and survival times were 120 days and 201 days, respectively. No significant correlation was found between mean number of AgNORs per nucleus or AgNOR size and remission rate, remission duration, or survival time. This study indicates that AgNOR staining is not a useful prognostic factor for cats with intestinal lymphoma.