A retrospective study of chemotherapeutic effect without wide-margin surgery or radiation therapy in dogs with oral malignant melanoma.

Background: Effective treatment for canine oral malignant melanoma (e.g., curative-intent surgery) may not be feasible or radiation therapy may be unavailable. However, chemotherapy is usually an option, and more information is needed regarding its use without adequate local treatments. Objective: Our objective was to investigate the efficacy of chemotherapy in canine oral malignant melanoma without adequate local control, using carboplatin with dose reduction in small-breed dogs and metronomic chemotherapy. Animals and procedure: Client-owned dogs with histopathologically diagnosed oral malignant melanoma were retrospectively enrolled from 2016 to 2022. The chemotherapy protocol in each case was determined by the attending clinician. Results: Thirteen dogs were included. The median progression-free interval of all 13 dogs was 42 d (14 to 953 d). The median overall survival time of dogs with chemotherapy as their only systemic treatment was 181 d (50 to 960 d; n = 11). The median dosage of carboplatin was 250 mg/m2. Response to treatment and clinical stage were significant prognostic factors. Conclusion and clinical relevance: As chemotherapy provided a median survival of 6 mo, it could be considered when adequate local control is infeasible. Earlier clinical stages or achievement of at least stable disease during chemotherapy may indicate better survival in dogs.

Une étude rétrospective de l'effet chimiothérapeutique sur le mélanome malin buccal canin dépourvu de chirurgie et de radiothérapie á large marge : le stade clinique et la réponse au traitement prédisent les résultats du patient. Mise en contexte: Des traitements efficaces pour le mélanome malin oral canin, tels que la chirurgie á visée curative, ne sont parfois pas réalisables ou la radiothérapie n'est pas disponible dans certaines régions. La chimiothérapie reste une option de traitement et davantage d'informations devraient être fournies pour les cas qui n'ont pas eu accés á un traitement local adéquat. Objectif: Cette étude visait á étudier l'efficacité de la chimiothérapie dans le mélanome malin oral canin sans contrôle local adéquat, en utilisant le carboplatine avec réduction de dose chez les chiens de petite race et la chimiothérapie métronomique. Animaux et procédure: Treize chiens appartenant á des clients atteints d'un mélanome malin oral diagnostiqué par histopathologie ont été rétrospectivement inscrits de 2016 á 2022. Le protocole de chimiothérapie a été déterminé par le clinicien traitant. Résultats: L'intervalle médian sans progression des treize chiens était de 42 jours (14­953 jours). La durée médiane de survie globale des chiens ayant reçu une chimiothérapie comme seul traitement systémique était de 181 jours (50­960 jours; n = 11). La dose médiane de carboplatine était de 250 mg/m2. La réponse au traitement et le stade clinique étaient des facteurs pronostiques importants. Conclusion et pertinence clinique: La chimiothérapie pouvait encore être envisagée lorsqu'un contrôle local adéquat était impossible. Des stades cliniques plus précoces ou des patients atteignant au moins une maladie stable pendant la chimiothérapie peuvent indiquer une meilleure survie.(Traduit par les auteurs).

Limited Clinical Efficacy with Potential Adverse Events in a Pilot Study of Autologous Adoptive Cell Therapy in Canine Oral Malignant Melanoma.

Adoptive cell therapy (ACT) has been studied in several human and canine cancers with some promising clinical outcomes but not in canine oral malignant melanoma (OMM). Our manuscript aimed to explore one kind of ACT, the ex vivo-expanded autologous immune cell infusion in canine OMM, as this tumor remains a treatment dilemma. The study recruited dogs with histopathological diagnoses of oral malignant melanoma, generated their peripheral blood mononuclear cells, expanded them into predominantly non-B non-T cells via stimulations of IL-15, IL-2, and IL-21, and then re-infused the cells into tumor-bearing dogs. Ten dogs were enrolled; three dogs did not report any adverse events; three had a mildly altered appetite; one had a mildly increased liver index, while the other three developed suspected anaphylaxis at different levels. The median progression-free interval was 49 days. Dogs with progressive disease during treatment had a shorter survival. This pilot study indicates limited efficacy with potential adverse events of this ACT. Most recruited patients were in a later stage and had macroscopic disease, which might affect the treatment efficacy. Further exploration of this cell therapy in an adjuvant setting, with adequate protocol modification and standardization, could still be considered.

Increased plasma DR-70 (fibrinogen-fibrin degradation products) concentrations as a diagnostic biomarker in dogs with neoplasms.

BACKGROUND: Tumor biomarkers have used widely in clinical oncology in human medicine. Only a few studies have evaluated the clinical utility of tumor biomarkers for veterinary medicine. A test for fibrinogen and fibrin degradation products (DR-70) has been proposed as an ideal biomarker for tumors in humans. The clinical value of DR-70 for veterinary medicine however has yet to be determined. OBJECTIVES: Investigate the diagnostic value of DR-70 concentrations by comparing them between healthy dogs and dogs with tumors. ANIMALS: Two hundred sixty-three dogs with different types of tumors were included. Sixty healthy dogs also were recruited for comparison. METHODS: The DR-70 concentrations were measured in all recruited individuals by ELISA. Clinical conditions were categorized based on histopathology, cytology, ultrasound examination, radiology, clinical findings, and a combination of these tests. RESULTS: The median concentration of DR-70 was 2.130 ± 0.868 µg/mL in dogs with tumors, which was significantly higher than in healthy dogs (1.202 ± 0.610 µg/mL; P < .0001). With a cut-off of 1.514 µg/mL, the sensitivity and specificity of DR-70 were 84.03% and 78.33%, respectively. The area under curve was 0.883. The DR-70 concentration can be an effective tumor biomarker in veterinary medicine. CONCLUSIONS AND CLINICAL IMPORTANCE: Increased DR-70 concentrations were not affected by tumor type, sex, age, or body weight. However, in dogs with metastatic mast cell tumors and oral malignant melanoma, DR-70 concentrations were significantly increased. Additional studies, including more dogs with nonneoplastic diseases, are needed to further evaluate the usefulness of DR-70 as a tumor biomarker.

Are They Thinking Differently? The Perceptions and Differences in Medical Disputes between Veterinarians and Clients.

Medical disputes in veterinary practices are widespread; yet, a limited amount of research has been conducted to investigate the factors contributing to medical disputes. This study examined veterinarians' and clients' perceptions regarding risk factors and possible solutions to medical disputes. A total of 245 respondents from Taiwan, including 125 veterinarians and 120 clients, completed an electronic self-administered, semi-structured questionnaire in 2022. The questionnaire covered six dimensions: medical skills, complaint management, the attitudes of stakeholders during interactions, medical expenses, clients' perspectives, and communication modes. The results highlighted significant differences in the perceptions of risk factors for inducing medical disputes and possible solutions between clients and veterinarians in veterinary practice. First, young veterinarians and clients perceived medical skills as the highest risk factor for inducing medical disputes, while experienced veterinarians disagreed (p < 0.001). In addition, veterinarians with medical dispute experience identified stakeholders' attitudes during interactions as the top contributing factor. Second, regarding possible solutions, all veterinarians preferred offering clients cost estimates and cultivating empathy and compassion towards them. On the other hand, clients underscored the importance of obtaining informed consent for treatments and expenses and suggested that veterinarians should supply comprehensive written information to facilitate this process. This study underlies the importance of understanding stakeholders' perceptions to mitigate medical disputes and advocates for improved communication education and training for young veterinarians. These findings provide valuable insights for veterinarians and clients, contributing to preventing and managing medical disputes in veterinary practices.

Perceptions of Veterinarians and Veterinary Students on What Risk Factors Constitute Medical Disputes and Comparisons between 2014 and 2022.

This study compared the risk perceptions of medical disputes among veterinarians and veterinary students in Taiwan between 2014 and 2022. Online validity-tested questionnaires were used to collect data, with 106 (73 veterinarians and 33 students) and 157 (126 veterinarians and 31 students) surveys collected in 2014 and 2022, respectively. Respondents would be asked to rate their perceptions on how likely each risk factor constitutes a medical dispute according to their past experiences on a five-point Likert scale from 1 to 5: "Very unlikely, unlikely, neutral, likely, very likely." The results showed that overall risk perceptions increased significantly in 2022 compared to 2014, with the top risk factors being attitudes during interactions and complaint management among experienced veterinarians. In contrast, students considered medical skills and clients' perspectives as the top two risk factors, with complaints management ranking as the least significant factor. The findings suggest that effective communication and complaint management are crucial in preventing medical disputes, highlighting the importance of developing these skills in young veterinarians and veterinary students to reduce medical disputes. The study also recommends increasing practical experiences of medical disputes and complaint management in veterinary education to bridge the gap between the perceptions of experienced veterinarians and students.

Bibliometric Analysis of Veterinary Communication Education Research over the Last Two Decades: Rare Yet Essential.

Research of veterinary communication education is a relatively rare but important field, and its importance has been increasingly noticed recently. This study aims to describe the existing veterinary education research literature by adopting the systematic bibliometric approach. We conducted a comprehensive literature exploration on worldwide veterinary education and veterinary communication education publications in the Web of Science Core Collection database from 1 January 2000 to 31 December 2021. VOSviewer and EXCEL were used to identify trends and patterns in characteristics of the publications, including author affiliations and countries, and the publishing journals. Based on our search criteria, in the past 22 years, there have been 6006 veterinary education publications with 101 publications in 2000, 684 publications in 2021 (577% increase), and 677 communication-related publications with 9 publications in 2000, 107 publications in 2021 (1189% increase). The VOSviewer results indicate that both the United States and England were the most vigorous countries with close collaboration. Our results show the publication quantity has been increasing at a sharp slope rate over the past twenty years, which indicates the importance and growth of veterinary education and the veterinary communication education research field, and identifies the international collaborations among countries and institutions.

L-Asparaginase, Doxorubicin, Vincristine, and Prednisolone (LHOP) Chemotherapy as a First-Line Treatment for Dogs with Multicentric Lymphoma.

Cyclophosphamide exhibits the weakest therapeutic effect compared with vincristine and doxorubicin in the CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisolone) chemotherapeutic protocol for the treatment of canine lymphoma. Twenty dogs with multicentric lymphoma were treated using the LHOP protocol, which used l-asparaginase in place of cyclophosphamide, and the outcomes were historically compared with those of dogs that received CHOP chemotherapy in the same institution. No significant differences were found in age (p = 0.107), body weight (p = 0.051), sex (p = 0.453), clinical stage V (p = 1), substage b (p = 0.573), T-cell phenotype (p = 0.340), overall response (p = 1), and hypercalcaemia status (p = 1) between the LHOP and CHOP groups. The adverse effects of l-asparaginase were well tolerated and self-limiting. The median PFS (progression-free survival) and median ST (survival time) in the LHOP group were 344 days (range: 28-940 days) and 344 days (range: 70-940 days), respectively. The median PFS and median ST in the CHOP group were 234 days (range: 49-1822 days) and 314 days (range: 50-1822 days), respectively. The dogs that received LHOP chemotherapy had a significantly longer PFS than the dogs that received CHOP chemotherapy (p = 0.001). No significant difference was observed in ST between the LHOP and CHOP groups (p = 0.131). Our study findings thus indicate that the LHOP protocol can be used as a first-line chemotherapeutic protocol in canine multicentric lymphoma.

Association between weight change during initial chemotherapy and clinical outcome in dogs with multicentric lymphoma.

The majority of the known prognostic factors in dogs with lymphoma have been evaluated before treatment commences or at the time of diagnosis. Prognostic factors evaluated during the initial phase of treatment are less described but may provide important clinical information. In this retrospective study, 82 canine lymphoma patients were categorized according to the weight change between diagnosis and after 5 weeks of chemotherapy. Dogs that gained greater than 5% or lost greater than 5% of initial body weight were categorized as increased- or decreased-weight groups, respectively. Those in which weight changed less than 5% were categorized as the maintained-weight group. The median progression-free survival (PFS) in the increased-weight group, maintained-weight group and decreased-weight group was 226, 256 and 129 days, respectively. The decreased-weight group had significantly shorter PFS than the increased and maintained groups (P = .023, P = .003, respectively). The median survival time (ST) in the increased-weight group, maintained-weight group and decreased-weight group was 320, 339 and 222 days, respectively. There was no significant difference in ST among the three groups (P = .128). In Cox-regression results, weight change group and initial body weight were significant risk factors associated to PFS (P = .007, P = .001, respectively) while only patient's initial body weight was a significant risk factor to ST (P = .013). In conclusion, evaluation of initial body weight and weight changes over time can provide valuable information regarding PFS and ST in dogs with multicentric lymphoma.

Genome-wide DNA methylation analysis using MethylCap-seq in canine high-grade B-cell lymphoma.

DNA methylation is a comprehensively studied epigenetic modification and plays crucial roles in cancer development. In the present study, MethylCap-seq was used to characterize the genome-wide DNA methylation patterns in canine high-grade B-cell lymphoma (cHGBL). Canine methylated DNA fragments were captured and the MEDIUM-HIGH and LOW fraction of methylated DNA was obtained based on variation in CpG methylation density. In the MEDIUM-HIGH and LOW fraction, 2144 and 1987 cHGBL-specific hypermethylated genes, respectively, were identified. Functional analysis highlighted pathways strongly related to oncogenesis. The relevant signaling pathways associated with neuronal system were also revealed, echoing recent novel findings that neurogenesis plays key roles in tumor establishment. In addition, 14 genes were hypermethylated in all the cHGBL cases but not in the healthy dogs. These genes might be potential signatures for tracing cHGBL, and some of them have been reported to play roles in various types of cancers. Further, the distinct methylation pattern of cHGBL showed a concordance with the clinical outcome, suggesting that aberrant epigenetic changes may influence tumor behavior. In summary, our study characterized genome-wide DNA methylation patterns using MethylCap-seq in cHGBL; the findings suggest that specific DNA hypermethylation holds promise for dissecting tumorigenesis and uncovering biomarkers for monitoring the progression of cHGBL.

Outcome of Canine Multicentric Lymphoma after Single or Divided Treatment with Cyclophosphamide in Multidrug Chemotherapy.

Cyclophosphamide is commonly used in combination chemotherapy to treat dogs with lymphoma. The metabolite of cyclophosphamide, acrolein, can irritate urinary bladder and cause sterile hemorrhagic cystitis. Dividing the administration of cyclophosphamide across multiple days may reduce the concentration of this metabolite in urinary bladder and reduce the possibility of cystitis. However, the impact of the therapeutic effect of this modification is not evaluated and compared to traditional single maximum-tolerated dose regimen. Seventy-two dogs with multicentric lymphoma received either bolus doses or divided doses of cyclophosphamide were included in this study. The incidence of hemorrhagic cystitis between 2 cyclophosphamide treatment groups was not significantly different (P = .357). There was no statistical difference in progression-free survival and survival time between 2 groups (P = .267 and P = .346). This modification of cyclophosphamide administration did not reduce the side effect of cystitis or affect remission and survival times in lymphoma dogs.

Potential enhancement of host immunity and anti-tumor efficacy of nanoscale curcumin and resveratrol in colorectal cancers by modulated electro- hyperthermia.

BACKGROUND: Modulated electro-hyperthermia (mEHT) is a form of hyperthermia used in cancer treatment. mEHT has demonstrated the ability to activate host immunity by inducing the release of heat shock proteins, triggering apoptosis, and destroying the integrity of cell membranes to enhance cellular uptake of chemo-drugs in tumor cells. Both curcumin and resveratrol are phytochemicals that function as effective antioxidants, immune activators, and potential inhibitors of tumor development. However, poor bioavailability is a major obstacle for use in clinical cancer treatment. METHODS: This purpose of this study was to investigate whether mEHT can increase anti-cancer efficacy of nanosized curcumin and resveratrol in in vitro and in vivo models. The in vitro study included cell proliferation assay, cell cycle, and apoptosis analysis. Serum concentration was analyzed for the absorption of curcumin and resveratrol in SD rat model. The in vivo CT26/BALB/c animal tumor model was used for validating the safety, tumor growth curve, and immune cell infiltration within tumor tissues after combined mEHT/curcumin/resveratrol treatment. RESULTS: The results indicate co-treatment of mEHT with nano-curcumin and resveratrol significantly induced cell cycle arrest and apoptosis of CT26 cells. The serum concentrations of curcumin and resveratrol were significantly elevated when mEHT was applied. The combination also inhibited the growth of CT26 colon cancer by inducing apoptosis and HSP70 expression of tumor cells while recruiting CD3+ T-cells and F4/80+ macrophages. CONCLUSIONS: The results of this study have suggested that this natural, non-toxic compound can be an effective anti-tumor strategy for clinical cancer therapy. mEHT can enable cellular uptake of potential anti-tumor materials and create a favorable tumor microenvironment for an immunological chain reaction that improves the success of combined treatments of curcumin and resveratrol.

Development of an oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and association between genotypes and chemotherapy side effects.

Canine MDR1 gene mutations produce translated P-glycoprotein, an active drug efflux transporter, resulting in dysfunction or over-expression. The 4-base deletion at exon 4 of MDR1 at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G allele of the c.-6-180T＞G variation in intron 1 of MDR1 (single nucleotide polymorphism [SNP] 180) causes P-glycoprotein over-expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations are reported to be common in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. Genotype distribution in Taiwan was also investigated. An oligonucleotide microarray was successfully developed for the detection of both genotypes and was applied to clinical samples. No 4-base deletion mutant allele was detected in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all dog breeds, not only in collies. The chemotherapy adverse effect percentages of the SNP 180 T/T, T/G, and G/G genotypes were 16.7%, 6.3%, and 0%, respectively. This study describes an efficient way for MDR1 gene mutation detection, clarifying genotype distribution, and the association with chemotherapy.

Urothelial Carcinomas of the Urinary Bladder With Plasmacytoid or Rhabdoid Features and Tendency of Epithelial-Mesenchymal Transition in 3 Dogs.

Plasmacytoid and rhabdoid variants of urothelial carcinomas (UCs) of the urinary bladder have been described in humans with plasma cell-like or rhabdoid cellular appearance and aggressive clinical outcome. Canine UC of the bladder is generally classified as papillary/nonpapillary and infiltrating/noninfiltrating with limited information regarding other histological patterns. We report 3 cases of UC of the urinary bladder showing a unique discohesive cellular morphology with malignant behavior resembling the human plasmacytoid and rhabdoid variants of UC, which may raise some difficulties in diagnosis. Epithelial-mesenchymal transition and reduced E-cadherin expression were revealed by immunohistochemistry in 2 cases, possibly explaining the discohesive and invasive behavior of the tumor cells. The findings broaden the morphological spectrum as well as the distinct clinical features of canine UC of the urinary bladder.

Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity.

Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.

Assessment of temporal association of relapse of canine multicentric lymphoma with components of the CHOP protocol: Is cyclophosphamide the weakest link?

Combination chemotherapy, using cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), is the most commonly used treatment for canine lymphoma. Most affected dogs respond during the initial stages of chemotherapy, but many relapse. The aim of this study was to evaluate the relationship between the use of specific chemotherapy drugs and clinical relapse, using the modified Madison-Wisconsin, 25 week chemotherapy protocol. Forty-one of 68 dogs affected with multicentric lymphoma relapsed during the treatment period. Relapse occurred more frequently after the administration of cyclophosphamide (n = 24; P < 0.01), compared with vincristine (n = 9) or doxorubicin (n = 5). Therefore, the therapeutic outcome of traditional CHOP-based chemotherapy might be improved by replacing cyclophosphamide with other cytotoxic drugs.

Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine lymphoma.

Forty-four dogs with multicentric lymphoma were treated using a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) induction protocol or treated using a cyclophosphamide, mitoxantrone, vincristine, and prednisolone (CMOP) induction protocol. There was no statistical difference in signalment and the presence of historical negative prognostic factors between the groups. The median progression-free survival (PFS) in the CHOP and CMOP groups were 222 d and 162 d, respectively (P = 0.75). The median survival time (MST) of dogs in CHOP and CMOP groups were 318 d and 242 d, respectively (P = 0.63). Anorexia and diarrhea episodes were significantly higher in the CHOP group than in the CMOP group (P = 0.02 and P = 0.01, respectively). These results suggest that the CMOP protocol provides similar PFS, MST and causes fewer side effects compared to the CHOP protocol. Therefore, the CMOP protocol may be another treatment choice for canine multicentric lymphoma.

Comparaison de l'efficacité et de la toxicité de la doxorubicine et du mitoxantrone dans la chimiothérapie combinée pour le lymphome canin. Quarante-quatre chiens atteints d'un lymphome multicentrique ont été traités à l'aide d'un protocole d'induction au cyclophosphamide, à la doxorubicine, à la vincristine et à la prednisolone (CHOP) ou traités en utilisant un protocole d'induction à la cyclophosphamide, au mitoxantrone, à la vincristine et à la prednisolone (CMOP). Il n'y a eu aucune différence statistique dans le signalement et la présence des facteurs de pronostic négatifs historiques entre les groupes. La survie sans progression (SSP) médiane des groupes CHOP et CMOP était de 222 jours et de 162 jours, respectivement (P = 0,75). La durée de survie moyenne (DSM) des chiens des groupes CHOP et CMOP a été de 318 jours et de 242 jours, respectivement (P = 0,63). Les épisodes d'anorexie et de diarrhée ont été significativement plus élevés dans le groupe CHOP comparativement au groupe CMOP (P = 0,02 et P = 0,01, respectivement). Ces résultats suggèrent que le protocole CMOP offre une SSP et une DSM semblables tout en causant moins d'effets secondaires comparativement au protocole CHOP. Par conséquent, le protocole CMOP peut représenter un autre choix de traitement pour les lymphomes multicentriques canins.(Traduit par Isabelle Vallières).

Suppressive function of low-dose deguelin on the invasion of oral cancer cells by downregulating tumor necrosis factor alpha-induced nuclear factor-kappa B signaling.

BACKGROUND: Deguelin has both antiproliferation and antimetastasis activities. However, high-dose deguelin elicits many undesired side effects. The purpose of this study was to investigate whether the low-dose deguelin can prevent the metastasis of oral cancer. METHODS: The dose effects of deguelin on metastasis of oral cancer cells were analyzed by in vitro invasion assay and an orthotropic xenograft mouse model. The involvement of tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) signaling was examined by Western blot and reporter assay. RESULTS: Low-dose deguelin, which has minimal cytotoxicity, significantly inhibited the invasion and migration of oral cancer cells. These inhibitory effects of low-dose deguelin were mediated by suppressing TNF-α-induced activation of IκB kinase leading to the inhibition of IκB phosphorylation, NF-κB transcriptional activity, and matrix metalloproteinase-2 (MMP2) expression. The low-dose deguelin treatment significantly inhibited tumor growth and invasion without systemic toxicity. CONCLUSION: The low-dose deguelin suppressed the invasion and migration of oral cancer by downregulating TNF-α-induced NF-κB signaling. © 2015 Wiley Periodicals, Inc. Head Neck 38: E524-E534, 2016.

Simultaneous visual inspection for barometric whole-body plethysmography waveforms during pulmonary function testing in client-owned cats.

OBJECTIVES: For the purpose of applying a barometric whole-body plethysmography (BWBP) device as a routine clinical tool in client-owned cats, the objective of this study was to evaluate the methodological importance of simultaneous visual inspection (SVI) of graphic tracing. METHODS: To investigate the effect of SVI on the results obtained, 50 client-owned cats were included. Breath-by-breath analysis was conducted with BWBP software, and a commonly used rejection setting was chosen for automatic elimination (AE) of non-breath artefactual waveforms, according to tidal volume (TV), inspiratory and expiratory time, and the difference between inspiratory and expiratory volumes. During 10 mins of data recording, SVI for BWBP waveforms was performed to record manually time periods that were free of any artefacts. The two datasets derived from AE alone (AEA method) and AE plus SVI (SVI-AE method) were compared. The inter-observer effect on the process of SVI was evaluated on six cats. RESULTS: There were statistically significant differences (P <0.001) between the AEA and SVI-AE datasets for most BWBP parameters. Bland-Altman analysis of the parameter-enhanced pause (Penh) showed heterogeneous variances, indicating less agreement when the Penh values were large. Intra-individual coefficients of variation of Penh were significantly higher with the AEA method than with the SVI-AE method (61.1% vs 34.7%, respectively; P <0.001). Inter-observer agreement on the SVI process was excellent, and no statistically significant differences between the two observers were found for any BWBP parameters obtained by the SVI-AE method (P >0.05). CONCLUSIONS AND RELEVANCE: Visual inspection for BWBP waveforms in real time can reliably identify stable breathing signals in client-owned cats. The obtained results were significantly different when the SVI method was used in addition to AE. In the interpretation of BWBP parameters or comparison of measurements among studies, whether an SVI methodology was applied should be considered.

Plasminogen Activator Inhibitor-2 Plays a Leading Prognostic Role among Protease Families in Non-Small Cell Lung Cancer.

BACKGROUND: In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk. METHODS: We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non-small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients. RESULTS: In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort. CONCLUSIONS: We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients.

Functional assessment of expiratory flow pattern in feline lower airway disease.

Feline lower airway disease (FLAD) is a chronic respiratory disease of which there is a lack of information on functional assessment in current veterinary medicine. The purposes of this study were to investigate expiratory pattern and evaluate the diagnostic utility of functional parameters in cats with FLAD. Thirty-three client-owned cats (23 FLAD cats and 10 control cats) were studied. Under quiet tidal breathing, pseudo-tidal breathing flow-volume loop (pTBFVL) was obtained from a barometric whole body plethysmography (BWBP) device. There were significant differences in the shapes of expiratory, but not inspiratory, curves between FLAD and control cats. The incidence of the presence of concave expiratory curve indicating lower airway obstruction was 74% in FLAD cats. To assess the diagnostic utility of pTBFVL indices in cats with FLAD, area under the receiver-operator curve was 0.86 for PEF/EF50 (peak expiratory flow divided by expiratory flow at end expiratory volume plus 50% tidal volume); a cuff-off value of PEF/EF50 >1.51 distinguished normal from FLAD (73.9% sensitivity, 100% specificity). There were no significant differences in traditionally measured BWBP parameters (ie, enhanced pause) between cats with and without FLAD in the present study. In conclusion, underlying change on expiratory flow pattern during natural tidal breathing existed in FLAD cats, and selected pTBFVL indices were useful in discriminating FLAD from normal cats. Tidal breathing pattern depicted by pseudoflow-pseudovolume loops from a BWBP system could be a non-invasive tool for functional assessment in client-owned cats.