High-flow nasal cannula improves hypoxemia in dogs failing conventional oxygen therapy.

OBJECTIVE: A prospective clinical trial was performed to evaluate the efficacy and tolerance of high-flow nasal cannula (HFNC) in dogs with hypoxemia. ANIMALS: 20 client-owned dogs failing conventional oxygen therapy (COT). PROCEDURES: Patients admitted to the ICU for treatment of hypoxemic respiratory failure were enrolled in the study. PaO2, SPO2, respiratory rate (RR), and acute patient physiologic and laboratory evaluation scores were obtained at the time of COT failure and after initiation of HFNC. Complications and patient tolerance while receiving HFNC were also recorded. RESULTS: Compared to COT, the median PaO2 and SO2 were significantly higher when dogs were receiving HFNC (60.8 vs 135.6 mm Hg and 90.7% vs 99.25%, respectively). Dogs receiving HFNC had a significant reduction in median RR as compared to dogs undergoing COT (52 vs 36 breaths per minute). After the initiation of HFNC, all dogs showed clinical improvement as measured by PaO2, SO2, and RR. Of 20 dogs, 6 ultimately failed HFNC and mechanical ventilation was recommended. Nine dogs undergoing HFNC survived to discharge, and acute patient physiologic and laboratory evaluation scores had a significant positive severity correlation with death. Complications included pneumothorax in 1 dog. CLINICAL RELEVANCE: COT has limited flow rates due to airway irritation caused by room temperature, nonhumidified oxygen. HFNC uses vapor humidification and heated oxygen, allowing for higher flow rates. In people, HFNC is used as escalation of oxygen therapy when COT fails. Dogs treated with HFNC had significant improvements in PaO2, SO2, and RR as compared to COT. HFNC is well tolerated and effective in treating hypoxemia in dogs.

Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma.

PURPOSE: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. EXPERIMENTAL DESIGN: We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing. RESULTS: Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell-mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. CONCLUSIONS: Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.

Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma.

Glioblastoma are highly invasive and associated with limited therapeutic options and a grim prognosis. Using stem cells to extend current therapeutic strategies by targeted drug delivery to infiltrated tumors cells is highly attractive. This study analyzes the tumor homing and therapeutic abilities of clinical grade human mesenchymal stem cells (MSCs) in an orthotopic glioblastoma mouse model. Our time course analysis demonstrated that MSCs display a rapid targeted migration to intracerebral U87 glioma xenografts growing in the contralateral hemisphere within the first 48h hours after application as assessed by histology and 7T magnetic resonance imaging. MSCs accumulated predominantly peritumorally but also infiltrated the main tumor mass and targeted distant tumor satellites while no MSCs were found in other regions of the brain. Intratumoral application of MSCs expressing herpes simplex virus thymidine kinase followed by systemic prodrug application of ganciclovir led to a significant tumor growth inhibition of 86% versus the control groups (p<0.05), which translated in a significant prolonged survival time (p<0.05). This study demonstrates that human MSCs generated according to apceth's GMP process from healthy donors are able to target and provide a significant growth inhibition in a glioblastoma model supporting a potential clinical translation.

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial.

TREAT-ME-1, a Phase 1/2 open-label multicenter, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC), MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Immunological and inflammatory markers were also assessed. All patients (3 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 at one dose level on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer's instructions for 48─72 h after MSC_apceth_101 injection. Ten patients were treated with a total dose of 3.0 x 106 cells/kg MSC_apceth_101. 36 adverse events and six serious adverse events were reported. Five patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.8 months (95% CI: 0.5, 3.9 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (1 year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease.

Incidence of arterial catheter complications: a retrospective study of 35 cats (2010-2014).

OBJECTIVES: The aim of this study was to investigate the incidence of complications associated with arterial catheterization in cats in a veterinary hospital, and to document which factors may increase the incidence of complications. METHODS: Medical records at a referral veterinary hospital were retrospectively reviewed to identify cats that had an arterial catheter placed between January 2010 and October 2014. RESULTS: Thirty-five cats having 38 arterial catheters were included in the study. There was a relatively high incidence of minor complications (23.7%), with the most common being catheter occlusion. The incidence of major arterial catheter complications was low (2.63%). Duration of catheter use was positively correlated to the incidence of complications. There was also a significant correlation between catheters used for intensive care unit monitoring and incidence of complications. All cats with catheter complications survived to discharge. CONCLUSIONS AND RELEVANCE: The low incidence of major arterial catheter complications in this population of cats illustrates that arterial catheterization is a safe monitoring and diagnostic tool. The duration of catheter placement is significantly associated with the incidence of catheter complications.

The use of therapeutic plasma exchange to reduce serum bilirubin in a dog with kernicterus.

OBJECTIVE: To describe the use of a manual method of therapeutic plasma exchange to reduce total serum bilirubin, manage kernicterus, and halt progression of neurological dysfunction in a dog with immune-mediated hemolytic anemia (IMHA). CASE SUMMARY: A 5-year-old male neutered Lhasa Apso diagnosed with IMHA developed acute onset neurologic signs consistent with kernicterus. Manual therapeutic plasma exchange was performed in an attempt to reduce total serum bilirubin. The initial exchange was performed at a lower plasma exchange volume due to the dog's critical status and the dog's clinical signs progressed. More aggressive plasma exchange was performed that resulted in a reduction in total serum bilirubin and no further progression of neurologic signs. The dog was euthanized due to suspicion of permanent neurologic changes and need for further blood transfusions. Histopathology postmortem confirmed a diagnosis of kernicterus. NEW OR UNIQUE INFORMATION PROVIDED: Kernicterus secondary to hyperbilirubinemia is well described in people, but has rarely been reported in dogs. Therapeutic plasma exchange has been used for decades in people to rapidly decrease serum bilirubin when hyperbilirubinemia progresses to neurologic signs, but to the authors' knowledge this has not been described in a dog.

Evaluation of oxygen administration with a high-flow nasal cannula to clinically normal dogs.

OBJECTIVE To evaluate the safety and efficacy of oxygen administration by use of a high-flow nasal cannula (HFNC) in sedated clinically normal dogs. ANIMALS 6 healthy adult dogs undergoing routine dental prophylaxis. PROCEDURES Dogs were sedated with butorphanol tartrate and dexmedetomidine. An esophageal balloon catheter was inserted into the esophagus, a double-pronged nasal cannula was inserted into the nares, and a catheter was inserted into the dorsal pedal artery. Dogs were positioned in right lateral recumbency. After a 6-minute acclimation period, baseline blood gas values and transpulmonary pressure were measured. Dogs then received supplemental oxygen via conventional oxygen therapy (COT) at a rate of 100 mL/kg/min (COT-100 treatment) and an HFNC at a rate of 20 L/min (HF-20 treatment) and 30 L/min (HF-30 treatment). Arterial blood gas and transpulmonary pressure were measured after a 6-minute acclimation period for each oxygen delivery method. Radiographs were obtained before and after oxygen administration to evaluate gastric distension. RESULTS Median Pao2 was significantly higher for HF-20 (519.9 mm Hg) and HF-30 (538.1 mm Hg) treatments, compared with median Pao2 for the COT-100 treatment (202.9 mm Hg). The Pao2 did not differ significantly between the HF-20 and HF-30 treatments. There was no significant difference in Paco2 or change in transpulmonary pressure between baseline and any oxygen delivery method. CONCLUSIONS AND CLINICAL RELEVANCE In this study, HFNC appeared to be a safe and effective method for oxygen delivery to sedated healthy dogs. Further studies are needed to evaluate use of HFNCs for oxygen administration to hypoxemic patients.

Retrospective evaluation of the effect of high flow oxygen therapy delivered by nasal cannula on PaO2 in dogs with moderate-to-severe hypoxemia.

OBJECTIVE: To describe the effects of high flow oxygen therapy (HFOT) in canine patients failing traditional oxygen therapy (TOT). DESIGN: Retrospective study. SETTING: Private referral practice. ANIMALS: Six client-owned dogs with primary pulmonary hypoxemia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High flow oxygen was delivered by high flow nasal prongs to dogs assessed clinically to be failing TOTs. HFOT was able to significantly improve PaO2 compared to TOT in severely hypoxemic dogs (median, 133.75 mm Hg; range, 109.2-304.8) versus median 61.85 mm Hg (range, 52.3-71.8; xsP = 0.0412). Flow rates were significantly higher with HFOT compared to TOT (median, 688 mL/kg/min; range, 523-1,667 mL/kg/min) versus median 122 mL/kg/min (range, 80-208; P = 0.0412). Complications included patient discomfort requiring light sedation in 1/6 dogs and persistence of a pneumothorax in 1 dog. Hypoxemia resolved in 4/6 dogs. CONCLUSION: These data suggest HFOT is a viable clinical intervention for dogs with moderate-to-severe hypoxemia assessed to be failing TOT. Further studies are needed to determine if HFOT can be used as an alternative to mechanical ventilation in resource limited settings and to characterize the complications associated with this therapy.

Mountain laurel toxicosis in a dog.

OBJECTIVE: To describe a case of mountain laurel (Kalmia latifolia) toxicosis in a dog, including case management and successful outcome. CASE SUMMARY: A dog presented for vomiting, hematochezia, bradycardia, weakness, and ataxia, which did not improve with supportive treatment. Mountain laurel ingestion was identified as cause of clinical signs after gastrotomy was performed to remove stomach contents. Supportive treatment was continued and the dog made a full recovery. NEW OR UNIQUE INFORMATION PROVIDED: This report details a case of mountain laurel toxicosis in a dog, including management strategies and outcome, which has not been previously published in the veterinary literature.

Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey.

Streptococcus pneumoniae (S. pneumoniae) may cause severe and lethal infections months and years following stem cell transplantation (SCT). In a prospective survey over a 3.5-year period, we assessed the incidence, risk factors and outcome for invasive pneumococcal infection (IPI) following SCT. Fifty-one episodes of IPI were reported: 43 episodes after bone marrow transplantation (BMT) and 8 after peripheral blood stem cell transplantation (PBSCT); 35 after allogeneic SCT and 16 after autologous SCT. Seven IPI episodes, all bacteraemias, were defined as early, occurring 1-35 d (median 3 d) post transplantation. Forty-four episodes were defined as late (> or = 100 d post SCT), occurring 4 months to 10 years (median 17 months) post transplantation. The incidences of early and late IPI were 2.03/1000 and 8.63/1000 transplantations respectively (P = 0.001). A higher incidence of late IPI was observed after BMT than after PBSCT (10.99 versus 3.23/1000; P < 0.01) and after allogeneic versus autologous SCT (12.20 versus 4.60/1000; P < 0.01). There was a higher estimated incidence of IPI in allogeneic patients with than in those without graft-versus-host disease (GVHD) (18.85 versus 8.25/1000; P = 0.015). The mortality rate was 20%, including 2/7 of early and 8/44 of late IPI. S. pneumoniae is a rare but important complication during the aplastic phase after SCT. In conclusion, S. pneumoniae is a significant cause of morbidity late post-transplantation, especially in allogeneic patients, and particularly those with GVHD. The high IPI mortality rate, both early and late post-transplantation, requires preventive approaches, mainly effective immunization.