Allogeneic peripheral blood haematopoietic stem cell transplantation for the treatment of dogs with high-grade B-cell lymphoma.

Autologous peripheral blood haematopoietic stem cell transplantation (HCT) cures 33%-40% of dogs with high-grade B-cell lymphoma. We hypothesized, based on human allogeneic bone marrow transplantation literature, that transplanting dogs using canine donor leukocyte-matched CD34+ cells would lead to fewer relapses and increased cure rates. We retrospectively reviewed medical records of dogs diagnosed with high-grade B-cell lymphoma who received an identical allogeneic HCT. A total of 15 dogs transplanted at four facilities were identified. Five of fifteen dogs relapsed before transplant. The mean number of donor CD34+ cells/kg harvested and infused into recipient dogs was 8.0 × 106 /kg (range: 2.08 × 106 /kg-2.9 × 107 /kg). The median disease-free interval and overall survival of all dogs was 1095 days (range: 9-2920 days) and 1115 days (range: 9-2920 days), respectively. Two of five dogs, not in remission at transplant, died in the hospital. The median disease-free interval and overall survival of the remaining three dogs was 25 days (range: 15-250 days) and 1100 days (range: 66-1902 days), respectively. The median disease-free interval and overall survival of the 10 dogs who had not relapsed was 1235 days (range: 19-2920 days) and 1235 days (range: 19-2920 days), respectively. One dog died soon after discharge of presumed gastric-dilatation-volvulus. Eight of nine remaining dogs lived >4 yrs post-alloHCT, leading to a cure rate of 89%. Acute graft versus host disease was seen in three dogs. These results suggest that allogeneic HCT can cure ~50% more dogs than those treated with autologous HCT.

Allogeneic hematopoietic cell transplantation in a dog with acute large granular lymphocytic leukemia.

CASE DESCRIPTION: A 3-year-old 10-kg (22-lb) neutered male Cavalier King Charles Spaniel was referred because of an episode of acute vomiting and diarrhea. CLINICAL FINDINGS: On physical examination, mild splenomegaly and prominent submandibular and popliteal lymph nodes were detected. Complete blood cell count revealed a high WBC count, characterized by a moderate lymphocytosis with 62% unclassified cells and severe thrombocytopenia with macroplatelets. On cytologic evaluation, the unclassified cells were described as large, neoplastic lymphoid cells containing a large nucleus with lacy chromatin and a large amount of blue vacuolated cytoplasm containing sparse, very fine azurophilic granules. A diagnosis of acute large granular lymphocytic leukemia of splenic origin was made. TREATMENT AND OUTCOME: Following induction chemotherapy, the affected dog underwent allogeneic hematopoietic cell transplantation with dog leukocyte antigen-matched CD34+ cells harvested from a sibling of the same litter. Chimerism analysis revealed full donor engraftment within 2 weeks after transplantation that remained stable for at least 2 years, with the dog remaining apparently healthy at home. CLINICAL RELEVANCE: Acute leukemias in dogs are rapidly fatal diseases. If an appropriate donor can be located, allogeneic hematopoietic cell transplantation may offer a feasible treatment, although peripheral blood CD34+ cell harvesting requires the availability of cell separator machines and management of graft-versus-host disease with immunosuppressive agents.

First report: Yersinia enterocolitica recovered from canine tonsils.

Yersinia enterocolitica (Y. enterocolitica) is a known zoonotic pathogen and is often found in pig tonsils as the primary site of colonisation. In this study we investigated whether or not Y. enterocolitica could be recovered from canine tonsils. During a study on the prevalence of Y. enterocolitica in animal populations in Ireland, 144 canine tonsils and 72 canine rectal swabs were procured over a ten-month period and subjected to microbiological examination for the presence of this human pathogen. Molecular methods were used to determine virulence and all strains were negative for the chromosomally mediated virulence factor (ail) and plasmid-encoded adhesion molecule (pYad). Y. enterocolitica was recovered from 25 of 216 (12%) samples. Twenty-four strains were from tonsils along with one from a rectal swab. All were biotype 1A. Antimicrobial resistance profiling showed two of 25 (8%) were resistant to cephalothin and the remaining strains were resistant to ampicillin and cephalothin with six of these additionally resistant to streptomycin. Our evidence that a human pathogen may be harboured in the oral cavity of dogs' adds a new dimension to the epidemiology of this organism, identifying a potential public health risk following exposure to dogs.

A generalized Cramér-Rao lower bound for moving arrays.

By properly including the forward motion of the array in the signal model, improved bearing estimation performance for a towed line array can be obtained. The improvement is a consequence of utilizing the bearing information contained in the Doppler. In this paper, it is shown by use of the Cramér-Rao lower bound that, as the array moves forward, the variance on the bearing estimate for an array of pressure sensors decreases, and that if an array of pressure-vector sensors is used, a significant improvement over that obtained for the array using pressure sensors only is obtained.

An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells.

Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kappaB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.

Use of multigeneration-family molecular dog leukocyte antigen typing to select a hematopoietic cell transplant donor for a dog with T-cell lymphoma.

CASE DESCRIPTION: A 7-year-old Golden Retriever was examined because of anorexia, lethargy, vomiting, and gradual weight loss. CLINICAL FINDINGS: Splenomegaly, pancytopenia, high serum calcium concentration, and high alkaline phosphatase activity were detected. Magnetic resonance imaging revealed an enlarged mesenteric lymph node and increased signals from the bone marrow of the ilium and vertebral bodies. Histologic examination and immunophenotyping of biopsy specimens confirmed a stage V (b) T-cell malignant lymphoma. TREATMENT AND OUTCOME: Clinical remission was attained by use of 2 chemotherapy cycles, followed by an allogeneic hematopoietic cell transplant performed at 18 weeks after diagnosis. A donor was identified by molecular dog leukocyte antigen typing methods. The patient was conditioned with 2 fractions of 4 Gy total body irradiation delivered 3 hours apart at 7 cGy/min, followed by an IV infusion of recombinant canine granulocyte colony-stimulating factor mobilized leukapheresis product and postgrafting immunosuppression with cyclosporine. Chimerism analyses revealed full donor engraftment that has been maintained for at least 58 weeks after transplant. Remission has been confirmed by normal results of serum thymidine kinase assays and the absence of peripheral blood clonal T-cell receptor gene rearrangements. CLINICAL RELEVANCE: Systemic chemotherapy induces remissions; however, most dogs succumb to disease recurrence because of multidrug resistance. Outcome of allogeneic hematopoietic cell transplantation in dogs can be excellent because of improved donor-recipient selection by use of molecular dog leukocyte antigen typing, compared with early attempts, and better prevention of graft versus host disease, better supportive care, and substitution of peripheral blood mononuclear cells for bone marrow.