First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

BACKGROUND: There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. METHODS: We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. RESULTS: Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3 months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0 months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). CONCLUSION: IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Real-world efficacy and safety of cabozantinib following immune checkpoint inhibitor failure in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Real-world data of cabozantinib after failure of immune checkpoint inhibitors for advanced renal cell carcinoma in Japanese population are limited. Additionally, prognostic factors of cabozantinib in this setting are still unknown. METHODS: We retrospectively evaluated data of 56 patients treated with cabozantinib subsequent to failed immune checkpoint inhibitors at four institutions. Regarding the efficacy profile, progression-free survival, overall survival and objective response rate were assessed. In terms of the safety profile, rate of adverse events, dose reduction and treatment interruption were assessed. Furthermore, risk factors of progression-free survival were analyzed. RESULTS: Twenty-nine patients (52%) were treated with cabozantinib as second-line therapy. Most frequent prior immune checkpoint inhibitor treatment was nivolumab plus ipilimumab combination therapy as first-line therapy (n = 30, 54%). Median progression-free survival and overall survival were 9.76 and 25.5 months, respectively, and objective response rate was 34%. All patients experienced at least one adverse event, and grade ≥ 3 adverse events were observed in 31 patients (55%). Forty-four (79%) and 31 (55%) patients needed dose reduction and treatment interruption, respectively. Multivariate analysis showed that reduced initial dose (i.e. <60 mg) (hazard ratio: 2.50, P = 0.0355) and presence of lymph node metastasis (hazard ratio: 2.50, P = 0.0172) were independent factors of shorter progression-free survival. CONCLUSION: Cabozantinib in Japanese patients with advanced renal cell carcinoma who failed immune checkpoint inhibitors was efficacious and had a manageable safety profile. These results appear to be similar to those of previous clinical trials.

Impact of sex on prognosis in patients with advanced renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. METHODS: We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. RESULTS: Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P < 0.0001). CONCLUSIONS: This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Association between lung immune prognostic index and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab.

INTRODUCTION AND OBJECTIVE: Lung immune prognostic index score (LIPI), calculated using the derived neutrophil-lymphocyte ratio and lactate dehydrogenase level, is reported for use in numerous malignancies, while its role on metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains limited. We aimed to investigate association between LIPI and outcomes in this setting. METHODS: We retrospectively evaluated 90 patients with mUC treated with pembrolizumab at four institutions. The associations between three LIPI groups and progression-free survival (PFS), overall survival (OS), objective response rates (ORRs) or disease control rates (DCRs) were assessed. RESULTS: Based on the LIPI, good, intermediate, and poor groups were observed in 41 (45.6%), 33 (36.7%), and 16 (17.8%) patients, respectively. The PFS and OS were significantly correlated with the LIPI (median PFS: 21.2 vs. 7.0 vs. 4.0 months, p = 0.001; OS: 44.3 vs. 15.0 vs. 4.2 months, p < 0.001 in the LIPI good vs. intermediate vs. poor groups). Multivariable analysis further revealed that LIPI good (vs. intermediate or poor, hazard ratio: 0.44, p = 0.004) and performance status = 0 (p = 0.015) were independent predictors of a longer PFS. In addition, LIPI good (hazard ratio: 0.29, p < 0.001) were shown to be associated with a longer OS together with performance status = 0 (p < 0.001). The ORRs tended to be different among patients with Good LIPI compared with Poor, and DCRs were significantly different among the three groups. CONCLUSIONS: LIPI, a simple and convenient score, could be a significant prognostic biomarker of OS, PFS, and DCRs for mUC treated with pembrolizumab.

Nondesulfurizing benzothiophene biotransformation to hetero and homodimeric ortho-substituted diaryl disulfides by the model PAH-degrading Sphingobium barthaii.

Understanding the biotransformation mechanisms of toxic sulfur-containing polycyclic aromatic hydrocarbon (PASH) pollutants such as benzothiophene (BT) is useful for predicting their environmental fates. In the natural environment, nondesulfurizing hydrocarbon-degrading bacteria are major active contributors to PASH biodegradation at petroleum-contaminated sites; however, BT biotransformation pathways by this group of bacteria are less explored when compared to desulfurizing organisms. When a model nondesulfurizing polycyclic aromatic hydrocarbon-degrading soil bacterium, Sphingobium barthaii KK22, was investigated for its ability to cometabolically biotransform BT by quantitative and qualitative methods, BT was depleted from culture media but was biotransformed into mostly high molar mass (HMM) hetero and homodimeric ortho-substituted diaryl disulfides (diaryl disulfanes). HMM diaryl disulfides have not been reported as biotransformation products of BT. Chemical structures were proposed for the diaryl disulfides by comprehensive mass spectrometry analyses of the chromatographically separated products and were supported by the identification of transient upstream BT biotransformation products, which included benzenethiols. Thiophenic acid products were also identified, and pathways that described BT biotransformation and novel HMM diaryl disulfide formation were constructed. This work shows that nondesulfurizing hydrocarbon-degrading organisms produce HMM diaryl disulfides from low molar mass polyaromatic sulfur heterocycles, and this may be taken into consideration when predicting the environmental fates of BT pollutants.

Underwater analysis of the reproductive behaviour and egg development of the jawfish Opistognathus iyonis.

Fishes of the jawfish family Opistognathidae are cryptobenthic and distributed in subtropical seas, and new species are still being reported. Opistognathus spp. live alone in burrows and males orally brood their egg clutches. The life cycle of jawfish, including their reproductive behaviour, is poorly understood. Here we describe the natural reproduction and embryonic development of Opistognathus iyonis in Yamaguchi, Japan, based on underwater surveys for 3 years. Spawning was observed as female jawfish came into the male's burrow ~30 min before sunrise. The jawfish had a mean number of 4.4 egg clutches in the burrow through 48.2 days, and the egg took 12 days to hatching. The mean temperature for developmental days was 20.8°C. The mean and cumulative water temperature during development significantly correlated with the number of developmental days. During egg development, male jawfish took care of eggs by holding them for part of the time in their mouths. Hatching was observed ~20 min after sunset. When hatching occurred orally, eggs were pushed out and back repeatedly using the lower jaw; consequently, the egg clutches were let out in an upward direction. To our best knowledge, this is the first report of the reproductive behaviour of O. iyonis in the natural environment in the same area for several years.

Outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma: a real-world multi-institution data with a minimum of 2 years of follow-up.

OBJECTIVES: To investigate the long-term follow-up outcomes of nivolumab monotherapy for previously treated metastatic renal cell carcinoma, using real-world data. METHODS: A total of 121 patients were treated with nivolumab monotherapy as subsequent therapy after the failure of prior tyrosine kinase inhibitor therapy between January 2013 and December 2021 at four affiliated institutions. To evaluate the outcome after 2 years or more, we selected patients in whom nivolumab therapy was started in December 2019 or earlier because data collection was performed until the end of December 2021. RESULTS: Seventy-four patients were evaluated. During the median follow-up period of 25.8 months, 62 (84%) and 40 (54%) patients had disease progression and died, respectively. Nivolumab was administered as second-line therapy in 43 patients (58%). The median progression-free survival and overall survival were 5.52 and 31.1 months, respectively, and objective response rate was 36%. There was no difference in progression-free survival or overall survival based on the treatment line of nivolumab (P = 0.915, P = 0.559). The magnitude of tumor response and development of immune-related adverse events were significantly associated with progression-free survival (P < 0.0001, P < 0.0001, respectively) and overall survival (P < 0.0001, P = 0.0002, respectively). Treatment-related adverse events developed in 38 patients (51%), including 33 (45%) who had immune-related adverse events. Steroid administration was needed in nine patients (12%). CONCLUSIONS: The present real-world multi-institution study with long-term follow-up data demonstrates that nivolumab monotherapy is effective for previously treated metastatic renal cell carcinoma, prolonging survival, improving tumor response and has a manageable safety profile.

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVES: To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. PATIENTS AND METHODS: Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. RESULTS: During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). CONCLUSIONS: The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Pedigree study of the heredity of copper-associated hepatitis in Dalmatians in Japan.

The pedigrees of 3 Dalmatian dogs afflicted with copper-associated hepatitis were investigated to discover the mode of inheritance. A composite family pedigree showed that the 3 affected Dalmatians were related. None of the parents of the affected dogs showed clinical symptoms of liver disease, and the disease had no sex predisposition. The estimated segregation ratio was approximately 3:1 based on surviving littermates. These findings suggested that the copper-associated hepatitis in these Dalmatians was an autosomal recessive mode of inheritance. In addition, some male Dalmatians imported from abroad might have been involved in the occurrence of this disease in Japan.

Étude généalogique de l'hérédité de l'hépatite associée au cuivre chez des Dalmatiens au Japon. Les pedigrees de trois chiens dalmatiens atteints d'hépatite associée au cuivre ont été étudiés pour découvrir le mode de transmission. Un pedigree familial composite a montré que les trois Dalmatiens affectés étaient apparentés. Aucun des parents des chiens affectés n'a présenté de symptômes cliniques de maladie du foie et la maladie n'avait aucune prédisposition associée au genre. Le ratio de ségrégation estimé était d'environ 3:1 sur la base des compagnons de portée survivants. Ces résultats suggèrent que l'hépatite associée au cuivre chez ces Dalmatiens était un mode de transmission autosomique récessif. De plus, certains dalmatiens mâles importés de l'étranger pourraient avoir été impliqués dans l'apparition de cette maladie au Japon.(Traduit par Dr Serge Messier).

Association of tumor burden with outcome in first-line therapy with nivolumab plus ipilimumab for previously untreated metastatic renal cell carcinoma.

OBJECTIVES: To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). METHODS: We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. RESULTS: The median tumor burden was 63.0 cm (interquartile range: 34.2-125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73-9.70] vs. 12.5 [4.77-24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11-4.45], P = 0.0242). CONCLUSIONS: Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Tenovin-6 induces the SIRT-independent cell growth suppression and blocks autophagy flux in canine hemangiosarcoma cell lines.

Canine hemangiosarcoma (HSA) is a commonly occurring aggressive tumor stemming from the vascular endothelial cells and is considered to be a good model for a similar disease in humans, called angiosarcoma. In this study, we reviewed drug libraries to identify new signal transduction inhibitors that can suppress the cell growth of canine HSA in vitro. We observed that tenovin-6, a sirtuin (SIRT) inhibitor, inhibited cell proliferation and induced cell death in three canine HSA cell lines (JuB4, Re12, and Ud6). These effects were induced through G1 cell cycle arrest and caspase-3 activation. Although tenovin-6 is known as an inhibitor of SIRT1 and SIRT2, knockout (KO) of genes encoding SIRT1 and/or SIRT2 had no apparent impact on cell proliferation in canine HSA. In addition, tenovin-6 showed cell growth inhibition in SIRT KO cells, as well as parental cells. These results indicated the cytotoxicity of tenovin-6 was a SIRT-independent event. Instead, we found that tenovin-6 inhibited autophagy flux in canine HSA cells, as evidenced by the suppression of lysosomal proteolysis. These results suggested that tenovin-6 induces cell growth suppression in canine HSA cells by impairing the lysosomal function. Therefore, tenovin-6 could be used in a new therapeutic strategy to treat canine HSA.

Recurrence analysis of intraoperative acridine orange-photodynamic therapy for dogs with intranasal tumors.

Intraoperative acridine orange-photodynamic therapy (AO-PDT) and cribriform plate irradiation are used to treat canine intranasal tumors. The purpose of this study was to evaluate the effects of AO-PDT on intranasal tumors and the recurrence rate of tumors after this treatment. Treatments with AO-PDT were performed on 38 dogs through a narrow window of the dorsal nasal cavity. The median progression-free interval was 12 mo and recurrence was detected in 21 dogs. Based on computed tomography, recurrence in 16 dogs was biased to the following areas: lateral (n = 10), medial (n = 2), ventral (n = 0), rostral (n = 0), and caudal (n = 8). Side effects were mild and included subcutaneous emphysema and rhinitis. The median survival time was 24 mo. Although AO-PDT with cribriform irradiation is an effective treatment for intranasal tumors, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly.

Analyse de récurrence de la thérapie photodynamique peropératoire à l'acridine orange pour des chiens atteints de tumeurs intranasales. La thérapie photodynamique peropératoire à l'acridine orange (AO-PDT) et l'irradiation de la plaque cribriforme sont utilisées pour traiter les tumeurs intranasales canines. Le but de cette étude était d'évaluer les effets de l'AO-PDT sur les tumeurs intranasales et le taux de récidive des tumeurs après ce traitement. Des traitements avec AO-PDT ont été effectués sur 38 chiens à travers une fenêtre étroite de la cavité nasale dorsale. L'intervalle médian sans progression était de 12 mois et une récidive a été détectée chez 21 chiens. Sur la base de la tomodensitométrie, la récidive chez 16 chiens était biaisée dans les zones suivantes : latérale (n = 10), médiale (n = 2), ventrale (n = 0), rostrale (n = 0) et caudale (n = 8). Les effets secondaires étaient légers et comprenaient l'emphysème sous-cutané et la rhinite. La durée médiane de survie était de 24 mois. Bien que l'AO-PDT avec irradiation de la plaque cribriforme soit un traitement efficace pour les tumeurs intranasales, les techniques d'AO-PDT devraient être améliorées pour traiter la cavité nasale de manière plus uniforme et plus complète.(Traduit par Dr Serge Messier).

Establishment of a dog primary prostate cancer organoid using the urine cancer stem cells.

Dog spontaneously develop prostate cancer (PC) like humans. Because most dogs with PC have a poor prognosis, they could be used as a translational model for advanced PC in humans. Stem cell-derived 3-D organoid culture could recapitulate organ structures and physiology. Using patient tissues, a human PC organoid culture system was established. Recent study has shown that urine cells also possess the characteristic of stem cells. However, urine cell-derived PC organoids have never been produced. Therefore, we generated PC organoids using the dog urine samples. Urine organoids were successfully generated from each dog with PC. Each organoid showed cystic structures and resembled the epithelial structures of original tissues. Expression of an epithelial cell marker, E-cadherin, and a myofibloblast marker, α-SMA, was observed in the urine organoids. The organoids also expressed a basal cell marker, CK5, and a luminal cell marker, CK8. CD49f-sorted basal cell organoids rapidly grew compared with CD24-sorted luminal cell organoids. The population of CD44-positive cells was the highest in both organoids and the original urine cells. Tumors were successfully formed with the injection of the organoids into immunodeficient mice. Treatment with a microtubule inhibitor, docetaxel, but not a cyclooxygenase inhibitor, piroxicam, and an mTOR inhibitor, rapamycin, decreased the cell viability of organoids. Treatment with a Hedgehog signal inhibitor, GANT61, increased the radiosensitivity in the organoids. These findings revealed that PC organoids using urine might become a useful tool for investigating the mechanisms of the pathogenesis and treatment of PC in dogs.

A NOVEL SUPPORT DEVICE FOR HEAD IMMOBILIZATION DURING RADIATION THERAPY THAT IS APPLICABLE TO BOTH CATS AND DOGS.

Repeatable head immobilization is important for minimizing positioning error during radiation therapy for veterinary patients with head neoplasms. The purpose of this retrospective cross-sectional study was to describe a novel technique for head immobilization (Device II) and compare this technique with a previously described technique (Device I). Device II provided additional support by incorporating three teeth (vs. two teeth with Device I). Between 2011 and 2013, both devices were applied in clinically affected cats (Device I, n = 17; Device II, n = 11) and dogs (Device I, n = 85; Device II, n = 22) of various breeds and sizes. The following data were recorded for each included patient: variability in the angle of the skull (roll, yaw, and pitch), coordinates of the isocenter, and distance from the reference mark to the tumor. Devices I and II differed for skull angle variability during the treatment of dogs (roll, P = 0.0007; yaw, P = 0.0018; pitch, P = 0.0384) and for yaw of during the treatment of cats (P < 0.0001). In each case, Device II was superior to Device I. The distance from the reference mark to the center of the tumor was significantly decreased for Device II vs. Device I (dogs, P < 0.0001; cats, P = 0.0002). Device II also provided more accurate coordinates for the isocenter. Authors recommend the use of, Device II for future clinical patients.

Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study.

Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors.

Pour des tumeurs intra-nasales malignes, une thérapie photodynamique administrant de l'acridine orange pendant l'opération et une irradiation par mégavoltage aux plaques cribriforms: l'etude préliminaire. Le pronostic des tumeurs intra-nasales canines non traitées est défavorable. Cette étude avait pour objectif d'évaluer rétrospectivement l'efficacité de la résection marginale d'une tumeur associée à une thérapie photodynamique (TPD) administrant de l'acridine orange (AO) pendant l'opération et à 1 fraction de 5 Gy d'irradiation par mégavoltage dans le traitement des tumeurs intra-nasales malignes. En cas d'invasion des plaques cribriformes et/ou de présence de cornets autour des lésions cribriformes, une fraction supplémentaire de 20 Gy a été administrée pendant l'opération par faisceaux d'électrons. Six chiens ont été inclus dans l'étude. Deux chiens présentaient des tumeurs de stade I, un de stade II et trois de stade IV. La durée moyenne de survie sans récidive locale et de survie globale après le traitement étaient respectivement de 8,5 et 13 mois. Une nouvelle tumeur est apparue chez deux des six chiens, respectivement 4 et 7 mois après le traitement. Les effets indésirables étaient bénins (un cas d'emphysème sous-cutané et trois cas de rhinite. L'association de la thérapie par AO améliorerait la durée de contrôle de la tumeur chez les chiens présentant des tumeurs intra-nasales malignes marginalement résécables.(Traduit par les auteurs).

Quantitative evaluation of the biomechanical and viscoelastic properties of the dog patellar tendon in response to neuromuscular blockade at different stifle angles.

The patellar tendon (PT) is crucial for maintaining stability and facilitating movement in the stifle joint. Elastography has been recognized as a prominent method for evaluating PT properties in humans and dogs. The utilization of oscillation methods in canine studies remains limited despite their extensive documentation in human studies. Our study represents the first effort to quantitatively assess and compare the effects of muscle relaxant on the biomechanical and viscoelastic characteristics of the PT at varying stifle angles in living dogs. Five healthy female beagles were used in this study. Biomechanical (tone, stiffness, and decrement) and viscoelastic (relaxation time and creep) properties of the PT were measured using MyotonPRO (Myoton Ltd, Estonia) prior to and following administration of rocuronium (0.5 mg/kg/body weight) at normal, extended, and flexed positions. Rocuronium was selected for its safety, controllability, and widespread clinical use in veterinary anesthesia. Two-way analysis of variance showed that tone, stiffness, and decrement were significantly higher (P < 0.001) in the control group than in the muscle relaxation group. At the same time, relaxation time and creep were significantly lower (P < 0.001) in the control group than in the muscle relaxation group. The findings indicate that stifle angle position and muscle rexalant administration fundamentally alter the biomechanical loading conditions of the PT, leading to changes in its viscoelastic properties. Therefore, this novel quantitative data could benefit clinical settings that necessitate accurate and objective methods for risk identification and monitoring PT biomechanics in dogs.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: It remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). METHODS: We retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. RESULTS: Of the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. CONCLUSION: There is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Relationship between clinical parameters and malformations in dogs diagnosed with atlanto-axial instability.

Atlanto-axial instability is a common disease that affects toy-breed dogs. Most cases of atlanto-axial instability are congenital. Furthermore, patients with atlanto-axial instability are predisposed to other concurrent diseases. Therefore, this study aimed to retrospectively determine the presence of concurrent diseases in cases with atlanto-axial instability using imaging data and analyze the relationship between clinical parameters and the incidence of complex malformations. The clinical data and imaging findings of 41 toy-breed dogs diagnosed with atlanto-axial instability were analyzed using their medical records and imaging data. Occipital dysplasia (17/27), atlanto-occipital overlapping (22/34), dens dysplasia (27/41), Chiari-like malformation (8/34), syringomyelia (5/34), lateral ventricular enlargement (20/36), and intracranial arachnoid cyst (5/35) were observed in patients with atlanto-axial instability. The body weight of the patients in the groups with atlanto-occipital overlapping and lateral ventricular enlargement was lower than that of those in the groups without these diseases (1.78 ± 0.71 vs 2.71 ± 1.15 kg, P = 0.0269, 1.60 ± 0.40 vs 2.75 ± 1.08 kg, P = 0.001, respectively). Furthermore, when the correlation between the total number of concurrent diseases and the age at onset and body weight was examined, it became clear that lower body weight was associated with the incidence of a greater number of concurrent diseases. Thus, the findings of this study suggest that toy-breed dogs are more likely to present with complex malformations and should be evaluated carefully with additional examinations and treatment methods.

Finite element study on post-screw removal stress in toy poodle radius with different plate designs and screw arrangements.

Background: The study employs finite element analysis to investigate stress distribution in the radius of toy poodles after screw removal. The examination focuses on the biomechanical implications of varied screw hole configurations using 1.5 and 2.0-mm locking compression plates (LCPs) with notched head T-Plates. Aim: To provide a noninvasive approach to analyzing the immediate consequences of screw removal from the radius bone in toy poodles. Specifically, it explores the impact of varied plate designs and screw arrangements on stress distribution within the forelimb bones. Methods: The study constructs a three-dimensional bone model of the toy poodle's forelimb based on computed tomography (CT) images. Simulations were designed to replicate jumping and landing from a 40 cm height, comparing stress distribution in the radius post-screw removal. Results: The analysis reveals significant variations in stress distribution patterns between the two LCPs. The radius implanted with the 2.0-mm LCP displays a uniform stress distribution, contrasting with the 1.5-mm plates. Localized stress concentration is observed around the screw holes, while trabecular bone regions near the screw holes exhibit lower stress levels. Conclusion: The study highlights the plate designs and screw configurations that affect bone stress in toy poodle forelimbs post-screw removal. The findings provide valuable insights for veterinarians, aiding informed decisions in veterinary orthopedic practices.

Elucidation of the radius and ulna fracture mechanisms in toy poodle dogs using finite element analysis.

Fractures occurring in the distal radius and ulna of toy breed dogs pose distinctive challenges for veterinary practitioners, requiring specialized treatment approaches primarily based on anatomical features. Finite Element Analysis (FEA) was applied to conduct numerical experiments to determine stress distribution across the bone. This methodology offers an alternative substitute for directly investigating these phenomena in living dog experiments, which could present ethical obstacles. A three-dimensional bone model of the metacarpal, carpal, radius, ulna, and humerus was reconstructed from Computed Tomography (CT) images of the toy poodle and dachshund forelimb. The model was designed to simulate the jumping and landing conditions from a vertical distance of 40 cm to the ground within a limited timeframe. The investigation revealed considerable variations in stress distribution patterns between the radius and ulna of toy poodles and dachshunds, indicating notably elevated stress levels in toy poodles compared to dachshunds. In static and dynamic stress analysis, toy poodles exhibit peak stress levels at the distal radius and ulna. The Von Mises stresses for toy poodles reach 90.07 MPa (static) and 1,090.75 MPa (dynamic) at the radius and 1,677.97 MPa (static) and 1,047.98 MPa (dynamic) at the ulna. Conversely, dachshunds demonstrate lower stress levels for 5.39 MPa (static) and 231.79 MPa (dynamic) at the radius and 390.56 MPa (static) and 513.28 MPa (dynamic) at the ulna. The findings offer valuable insights for modified treatment approaches in managing fractures in toy breed dogs, optimizing care and outcomes.