Background: Continuous administration of low doses of cyclophosphamide and standard doses of cyclooxygenase‐inhibiting drugs has been shown to suppress tumor angiogenesis, reverse immunosuppression, ...and deplete regulatory T cells in cancer models.
Hypothesis: We hypothesized that continuous treatment with low‐dose cyclophosphamide and full‐dose piroxicam would delay tumor recurrence in dogs with soft tissue sarcomas (STS).
Animals: Eighty‐five dogs with incompletely resected STS, 30 treated dogs, and 55 contemporary control dogs.
Methods: Treatment outcomes in 85 dogs with incompletely resected STS were evaluated in a retrospective study. Dogs in the treatment group received continuously administered low‐dose cyclophosphamide (10 mg/m2) and standard dose piroxicam (0.3 mg/kg) therapy. Time to local tumor recurrence (disease‐free interval; DFI) was compared between the 30 treated dogs and 55 untreated control dogs matched for age and tumor site and grade.
Results: DFI was significantly (P < .0001) prolonged for STS of all sites (trunk and extremity) in treated dogs compared with untreated control dogs. The DFI also was significantly longer in treated dogs when tumor site (trunk and extremity) was compared. Twelve treated dogs (40%) experienced mild toxicity (grade 1 and 2) at some point during treatment and 1 dog developed grade 4 cystitis. Every other day dosing was tolerated better than daily dosing.
Conclusions: Metronomic therapy with cyclophosphamide and piroxicam was very effective in preventing tumor recurrence in dogs with incompletely resected STS. These findings suggest that further evaluation of this approach is warranted as adjuvant therapy in dogs with highly metastatic tumors such as osteosarcoma and melanoma.
Background
KIT inhibitors, such as toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL ...or TOC is superior for treating MCT without c‐kit mutations.
Hypothesis/Objectives
To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c‐kit mutated MCT would have a better response to TOC than VBL.
Animals
Eighty‐eight client‐owned dogs with macroscopic MCT.
Methods
Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c‐kit mutation status using an adaptive randomization scheme.
Results
Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c‐kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 0.62–3.92; P = 0.28). Median progression‐free survival (PFS) for dogs receiving VBL was 78 days (7–1,521) and for TOC 95.5 (14–990); hazard ratio (HR) = 1.34 0.72–2.50; P = 0.36. Median overall survival (OS) was 241.5 days (10–1,521) for the VBL group and 159 (20–990) for the TOC group; HR = 0.80 (0.45–1.41; P = 0.44).
Conclusions and Clinical Importance
Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c‐kit mutations was not different between treatment groups in this population of dogs, c‐kit mutation status did not predict treatment response.
Regulatory T cells (Treg) are a distinct group of T lymphocytes with immunosuppressive properties that serve normally to prevent harmful autoimmune responses. However, Tregs can also interfere with ...beneficial immune responses such as anti-tumor and anti-viral immunity in humans and rodents. Given the overall importance of Tregs, it is likely that they play an important role in diseases of dogs as well. However, at present reagents required for identification of Tregs in dogs are not available. Therefore, we investigated whether expression of FoxP3, a transcription factor that is highly expressed in Tregs in humans and rodents could also be used to identify Tregs in dogs. We found that a cross-reactive FoxP3 antibody identified a subset of CD4+ T cells in blood and lymph nodes of dogs. By flow cytometry the mean percentage of FoxP3+CD4+ T cells in normal dogs was 4.3% in blood and 9.8% in the lymph nodes. In dogs with cancer, there was a significant increase in numbers of Treg in blood (7.5%) and tumor-draining lymph nodes (17.1%) compared to age-matched healthy control dogs. We also found that FoxP3+CD4+ T cells in dogs could be significantly expanded in vitro by TCR activation together with addition of TGF-β and IL-2. Treated cells also significantly increased expression of TGF-β and IL-10mRNA. We conclude from these studies that a cross-reactive FoxP3 antibody can be used to identify Tregs in dogs and that this reagent may serve as a useful tool for investigating the role of Treg in a variety of diseases of dogs.
Increased numbers of tumour‐associated macrophages correlate with rapid tumour growth and metastasis in tumours. Thus, macrophage depletion has potential as a novel cancer therapy and positive ...responses have been reported in rodent tumour models. To investigate the effectiveness of this approach in dogs with cancer, we evaluated the effects of the macrophage‐depleting agent liposomal clodronate (LC) in dogs with soft‐tissue sarcoma (STS). To this end, we conducted a clinical trial of LC therapy in 13 dogs with STS. Repeated LC administration was well tolerated clinically. Preliminary examination of tumour biopsy sets from 5 of the 13 dogs demonstrated that the density of CD11b+ macrophages was significantly decreased after LC treatment. Circulating concentrations of interleukin‐8 were also significantly reduced. These preliminary studies are the first to suggest that LC can be used as a systemic macrophage‐depleting agent in dogs to reduce numbers of tumour‐associated macrophages.
The correlated electron material CePd2 P2 crystallizes in the ThCr2 Si2 structure and orders ferromagnetically at 29 K. Prior work by Lai et al. Phys. Rev. B 97, 224406 (2018) found evidence for a ...ferromagnetic quantum critical point induced by chemical compression via substitution of Ni for Pd. However, disorder effects due to the chemical substitution interfere with a simple analysis of the possible critical behavior. In the present paper, we examine the temperature-pressure-magnetic-field phase diagram of single crystalline CePd2 P2 to 25 GPa using a combination of resistivity, magnetic susceptibility, and x-ray diffraction measurements. We find that the ferromagnetism appears to be destroyed near 12 GPa, without any change in the crystal structure.
In vivo transfection of established tumors with immunostimulatory genes can elicit antitumor immunity. Therefore, we evaluated the safety and efficacy of intratumoral injections of a bacterial ...superantigen with a cytokine gene in dogs with malignant melanoma, a spontaneous and highly malignant canine tumor. 26 dogs with melanoma were treated with lipid-complexed plasmid DNA encoding staphylococcal enterotoxin B and either GM-CSF or IL-2. Dogs were evaluated for treatment-associated toxicity, tumor responses, immunologic responses, and survival times. The overall response rate (complete or partial remissions) for all 26 dogs was 46% (12 of 26), and was highest in patients with smaller tumors. Toxicity was minimal or absent in all dogs. Injected tumors developed marked infiltrates of CD4+ and CD8+ T cells and macrophages, and tumor regression was associated with development of high levels of antitumor cytotoxic T lymphocyte activity in peripheral blood lymphocytes. Survival times for animals with stage III melanomas treated by intratumoral gene therapy were prolonged significantly compared with animals treated with surgical tumor excision only. Thus, local tumor transfection with superantigen and cytokine genes was capable of inducing both local and systemic antitumor immunity in an outbred animal with a spontaneously developing malignant tumor.
Objective
Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the ...largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy.
Design
A retrospective review of clinical case notes.
Setting
Two tertiary fetal medicine centres.
Population
Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team.
Methods
We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient‐specific panels and interpreted using American College of Medical Genetics guidelines.
Results
A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy.
Conclusions
We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES.
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Prenatal exome sequencing can aid decision‐making in pregnancy management; review ahead of routine implementation in NHS.
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Prenatal exome sequencing can aid decision making in pregnancy management; review ahead of routine implementation in NHS.
To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy ...involving SCN9A.
An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals.
Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete.
Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.
The efficacy of three gastric restriction operations were compared in a prospective randomized study of 310 morbidly obese subjects. The median patient age was 34 years (range, 18 to 62 years). They ...were predominantly female (13:1) and had a median pre-operative weight that was 198% of their ideal weight (range, 160% to 318%). There was an equitable dispersion of perceived risk factors between the groups under study and there were no deaths during the perioperative period. Compliance with follow-up at 3 years was 91%. When success was defined as a loss of more than 50% of excess weight or a current pregnancy, the success rates at 3 years were 17% for gastrogastrostomy, 48% for vertical gastroplasty, and 67% for Roux-en-Y gastric bypass (p less than 0.001). Although the gastric bypass operation took longer to perform, there were similar outcome patterns for the three groups during the postoperative period. We conclude that the Roux-en-Y gastric bypass is the preferred procedure for the surgical treatment of morbid obesity.
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